腺苷A2A受体调控肾间质纤维化的机制研究
|
摘要
研究背景
各种形式的终末期肾病，无关他们的病因是什么，进行性的肾间质纤维化和肾小管萎缩是其共同的病理特征。肾间质纤维化由炎性因素促发，继之出现肾小管上皮细胞向间充质细胞转化。早期的抗炎治疗策略对于预防肾间质纤维化的进程及其重要。然而目前还没有有效的治疗策略可以采用，因此，寻找新的治疗靶点及其紧迫。
持续损伤后的肾脏炎症，例如IgA肾病和狼疮性肾炎，作为启动因素，建立了纤维化的舞台，促发了组织纤维化的发生。在这个病理过程中，炎性细胞，如单核巨噬细胞和淋巴细胞发挥了重要作用。肾间质纤维化特点就是肌成纤维细胞的激活和基质蛋白的沉积，主要包括I型胶原和III型胶原。在肾间质纤维化的病程中，通过EMT产生了大量的表达α-SMA肌成纤维细胞，其是基质蛋白的主要来源。单侧输尿管梗阻(UUO)模型一直被用来阐明肾间质纤维化的发生机制。单核巨噬细胞和淋巴细胞的浸润及淋巴细胞的功能失常在UUO诱导的肾间质纤维化的模型中起重要的致病作用。在这个模型中，细胞水平上，肾小管扩张导致肾小管上皮细胞失去上皮细胞的特点，并获得间充质细胞性状，如α-SMA的表达和肌动蛋白的重组。因此，肾小管上皮细胞通过EMT过程成为肾肌成纤维细胞的主要来源。在分子水平上，TGF-β1通过激活其下游的Rho/ROCK信号传导通路在EMT中起着关键的作用。
最近，腺苷A_(2A)的受体(A_(2A)R)作为一种新的炎症调节因子调控炎症过程和组织修复。药理学研究表明，A_(2A)R激动剂CGS21680和ATL193，可以有效地抑制炎症，激活A_(2A)R导致肾小球肾炎和肾脏损伤的减轻。此外，最近的研究发现，在肝星状细胞，激活A_(2A)R可以抑制Rho/ROCK1。以上所有表明，调控A_(2A)R对炎症、EMT事件起着重要的调节作用。因此，我们推测，激活A_(2A)R可以抑制炎症细胞浸润，EMT事件和促纤维化因子，从而防止随之而来的肾间质纤维化。相反，A_(2A)R失活可能导致肾间质纤维化恶化。
使用UUO引起的肾间质纤维化实验小鼠模型，我们从多方面评估了A_(2A)R在肾间质纤维化中的调节作用，包括间质淋巴细胞浸润，细胞EMT的生物标志物，促纤维化*本课题为国家自然科学基金资助项目. No30871170因子TGF-β1的表达及其下游Rho/ROCK1途径，以及由此产生的细胞外基质的积累。
研究目的
明确腺苷A_(2A)R对单侧输尿管梗阻(UUO)小鼠肾间质纤维化表型的影响。探讨腺苷A_(2A)R影响肾间质纤维化的分子机制。
方法
建立C57背景小鼠肾间质纤维化动态模型，采用HE染色、Masson染色、免疫组化对UUO术后3天、7天、14天三个时间结点进行病理学检测及纤维化程度进行评估，计算机辅助图像分析用于评估肾间质纤维化情况及炎性细胞浸润情况。
药理学干预实验，研究腺苷A_(2A)R对不同处理组表型的影响，采用敲除腺苷A_(2A)R及CGS21680激活腺苷A_(2A)R，对三个时间结点的不同处理组，包括假手术对照组、野生型+梗阻组、A_(2A)R激活+梗阻组、A_(2A)R敲除+梗阻组表型进行分析，明确A_(2A)R对肾间质纤维化表型的影响。
进一步明确腺苷A_(2A)R影响肾间质纤维化的分子机制，使用Western-blot、免疫组化对影响肾间质纤维化的关键环节，肾小管上皮细胞向间充质细胞转化(EMT)进行检测。动态监测肾小管上皮细胞标志E-cadherin及肌成纤维细胞的表面标志α-SMA的变化。
免疫组化明确EMT启动因素炎症细胞浸润的种类，image pro plus计算机辅助图像定量分析，分析A_(2A)R对不同组别细胞浸润的影响。
使用RT-qPCR检测腺苷A_(2A)R对致纤维化因子TGF-β1和RHO/ROCK1信号途径的影响。
结果
激活腺苷A_(2A)R减轻了细胞外基质胶原的沉积。
激活腺苷A_(2A)R抑制了EMT的进程。
激活腺苷A_(2A)R减少了促纤维化因子的表达。
腺苷A_(2A)R介导的肾间质纤维化保护作用源于激活腺苷A_(2A)R抑制了T淋巴细胞的浸润。
与之相反的是，A_(2A)R失活将对以上表型，发挥完全相反的作用。
结论
本研究首次在小鼠UUO模型中证实了激活A_(2A)R阻止肾间质纤维化的保护作用，靶向调控A_(2A)R是防治肾间质纤维化的又一个新的治疗策略。
Background
Regardless of the etiology, almost all forms of end stage renal disease share thecommon pathological feature of progressive renal interstitial fibrosis (RIF) and tubularatrophy. RIF is commonly triggered by inflammatory processes and succedentepithelial-mesenchymal transition (EMT). An early initiated anti-inflammatory strategy istherefore of the importance to prevent the progression of RIF, however, no therapeuticapproach is currently available to achieve this goal. Thus, exploring new therapeutic targetis in urgent need.
Renal inflammation after sustained injuries, e.g. IgA nephropathy and lupus nephritis,serves as a primer that sets up the fibrogenic stage and triggers tissue fibrogenesis. In thispathological progress inflammatory cells, such as macrophage and lymphocyte, play crucialroles. RIF is characterized by the myofibroblast activation and the accumulation of matrixproteins including collagen types I (Col I) and type III (Col III). While produced via theEMT event in the pathologic progress of RIF myofibroblast with identified expression ofα-SMA is the major source of the increased production of matrix protein in RIF. A unilateralureteral obstruction (UUO) model has been refined to elucidate the pathogenesis andmechanisms responsible for RIF. It has been shown that the infiltration of macrophages andT cells and lymphocyte dysfunction are two major mechanisms contributing toUUO-induced RIF model. In this model, at cellular level, tubular dilatation leads tubularepithelia lose their epithelial characteristics and acquire mesenchymal traits such as α-SMAexpression and actin reorganization. Therefore, tubular epithelial cells become the majorsource of renal myofibroblast during EMT process. At molecular level, TGF-β1plays a keyrole in EMT via activation of its downstream Rho/ROCK signaling pathway.
Recently, adenosine A_(2A) receptor (A_(2A)R) emerges as a novel inflammation regulatoraffecting on inflammation process and tissue repair. Pharmacology studies showed thatA_(2A)R agonist, CGS21680and ATL193, can effectively suppress inflammation. Activationof A_(2A)R leads to attenuation of glomerulonephritis and renal injury. Further, recent studyidentified that A_(2A)R activation inhibits Rho/ROCK1in hepatic stellate cells. All abovestrongly suggest that A_(2A)R manipulation plays an important regulatory role oninflammation on EMT event. Therefore, we hypothesize that activation of A_(2A)R maysuppress cellular infiltration, EMT event and profibrogenic factors, thereby to preventconsequent pathology of RIF. Conversely, inactivation of A_(2A)R may lead exacerbation ofRIF.
Using experimental UUO-induced RIF mouse model, we evaluated the modulatoryeffect of A_(2A)R-based manipulation on several aspects of RIF progression, includinginterstitial lymphocyte infiltration, cellular biomarkers of EMT, expression of profibrogenicfactor TGF-β1and its downstream Rho/ROCK1pathway, as well as the consequentextracellular matrix accumulation.
Methods
To test this hypothesis we applied unilateral ureteral obstruction (UUO) model of RIFon A_(2A)R knockout mice and their littermates, and combined the intervention of selectiveA_(2A)R agonist, CGS21680. At the day3,7and14post-RIF model establishment, weevaluated the effects of A_(2A)R manipulation on molecular pathological progress of RIF,including imunohistochemistry of collagen types I, III, α-SMA and CD4+T lymphocyte,CD4+CD25+FoxP3+regulatory T cells (Treg), Western blot of E-cadherin and α-smoothmuscle actin (α-SMA), and quantitative PCR for ROCK1and TGF-β1mRNAmeasurement.
Results
Our data showed that activation of A_(2A)R significantly suppressed the deposition ofcollagen types I, III, the infiltration of CD4+T lymphocytes as well as the expression ofTGF-β1and ROCK1that inhibited and postponed the process of EMT. Conversely, geneticinactivation of A_(2A)R exacerbated aforementioned pathophysiological processes of RIF.
Conclusion
Together, activation of A2AR effectively alleviated EMT and RIF in mice, suggestingA2AR as a potential therapeutic target for the treatment of RIF.
各种形式的终末期肾病，无关他们的病因是什么，进行性的肾间质纤维化和肾小管萎缩是其共同的病理特征。肾间质纤维化由炎性因素促发，继之出现肾小管上皮细胞向间充质细胞转化。早期的抗炎治疗策略对于预防肾间质纤维化的进程及其重要。然而目前还没有有效的治疗策略可以采用，因此，寻找新的治疗靶点及其紧迫。
持续损伤后的肾脏炎症，例如IgA肾病和狼疮性肾炎，作为启动因素，建立了纤维化的舞台，促发了组织纤维化的发生。在这个病理过程中，炎性细胞，如单核巨噬细胞和淋巴细胞发挥了重要作用。肾间质纤维化特点就是肌成纤维细胞的激活和基质蛋白的沉积，主要包括I型胶原和III型胶原。在肾间质纤维化的病程中，通过EMT产生了大量的表达α-SMA肌成纤维细胞，其是基质蛋白的主要来源。单侧输尿管梗阻(UUO)模型一直被用来阐明肾间质纤维化的发生机制。单核巨噬细胞和淋巴细胞的浸润及淋巴细胞的功能失常在UUO诱导的肾间质纤维化的模型中起重要的致病作用。在这个模型中，细胞水平上，肾小管扩张导致肾小管上皮细胞失去上皮细胞的特点，并获得间充质细胞性状，如α-SMA的表达和肌动蛋白的重组。因此，肾小管上皮细胞通过EMT过程成为肾肌成纤维细胞的主要来源。在分子水平上，TGF-β1通过激活其下游的Rho/ROCK信号传导通路在EMT中起着关键的作用。
最近，腺苷A_(2A)的受体(A_(2A)R)作为一种新的炎症调节因子调控炎症过程和组织修复。药理学研究表明，A_(2A)R激动剂CGS21680和ATL193，可以有效地抑制炎症，激活A_(2A)R导致肾小球肾炎和肾脏损伤的减轻。此外，最近的研究发现，在肝星状细胞，激活A_(2A)R可以抑制Rho/ROCK1。以上所有表明，调控A_(2A)R对炎症、EMT事件起着重要的调节作用。因此，我们推测，激活A_(2A)R可以抑制炎症细胞浸润，EMT事件和促纤维化因子，从而防止随之而来的肾间质纤维化。相反，A_(2A)R失活可能导致肾间质纤维化恶化。
使用UUO引起的肾间质纤维化实验小鼠模型，我们从多方面评估了A_(2A)R在肾间质纤维化中的调节作用，包括间质淋巴细胞浸润，细胞EMT的生物标志物，促纤维化*本课题为国家自然科学基金资助项目. No30871170因子TGF-β1的表达及其下游Rho/ROCK1途径，以及由此产生的细胞外基质的积累。
研究目的
明确腺苷A_(2A)R对单侧输尿管梗阻(UUO)小鼠肾间质纤维化表型的影响。探讨腺苷A_(2A)R影响肾间质纤维化的分子机制。
方法
建立C57背景小鼠肾间质纤维化动态模型，采用HE染色、Masson染色、免疫组化对UUO术后3天、7天、14天三个时间结点进行病理学检测及纤维化程度进行评估，计算机辅助图像分析用于评估肾间质纤维化情况及炎性细胞浸润情况。
药理学干预实验，研究腺苷A_(2A)R对不同处理组表型的影响，采用敲除腺苷A_(2A)R及CGS21680激活腺苷A_(2A)R，对三个时间结点的不同处理组，包括假手术对照组、野生型+梗阻组、A_(2A)R激活+梗阻组、A_(2A)R敲除+梗阻组表型进行分析，明确A_(2A)R对肾间质纤维化表型的影响。
进一步明确腺苷A_(2A)R影响肾间质纤维化的分子机制，使用Western-blot、免疫组化对影响肾间质纤维化的关键环节，肾小管上皮细胞向间充质细胞转化(EMT)进行检测。动态监测肾小管上皮细胞标志E-cadherin及肌成纤维细胞的表面标志α-SMA的变化。
免疫组化明确EMT启动因素炎症细胞浸润的种类，image pro plus计算机辅助图像定量分析，分析A_(2A)R对不同组别细胞浸润的影响。
使用RT-qPCR检测腺苷A_(2A)R对致纤维化因子TGF-β1和RHO/ROCK1信号途径的影响。
结果
激活腺苷A_(2A)R减轻了细胞外基质胶原的沉积。
激活腺苷A_(2A)R抑制了EMT的进程。
激活腺苷A_(2A)R减少了促纤维化因子的表达。
腺苷A_(2A)R介导的肾间质纤维化保护作用源于激活腺苷A_(2A)R抑制了T淋巴细胞的浸润。
与之相反的是，A_(2A)R失活将对以上表型，发挥完全相反的作用。
结论
本研究首次在小鼠UUO模型中证实了激活A_(2A)R阻止肾间质纤维化的保护作用，靶向调控A_(2A)R是防治肾间质纤维化的又一个新的治疗策略。
Background
Regardless of the etiology, almost all forms of end stage renal disease share thecommon pathological feature of progressive renal interstitial fibrosis (RIF) and tubularatrophy. RIF is commonly triggered by inflammatory processes and succedentepithelial-mesenchymal transition (EMT). An early initiated anti-inflammatory strategy istherefore of the importance to prevent the progression of RIF, however, no therapeuticapproach is currently available to achieve this goal. Thus, exploring new therapeutic targetis in urgent need.
Renal inflammation after sustained injuries, e.g. IgA nephropathy and lupus nephritis,serves as a primer that sets up the fibrogenic stage and triggers tissue fibrogenesis. In thispathological progress inflammatory cells, such as macrophage and lymphocyte, play crucialroles. RIF is characterized by the myofibroblast activation and the accumulation of matrixproteins including collagen types I (Col I) and type III (Col III). While produced via theEMT event in the pathologic progress of RIF myofibroblast with identified expression ofα-SMA is the major source of the increased production of matrix protein in RIF. A unilateralureteral obstruction (UUO) model has been refined to elucidate the pathogenesis andmechanisms responsible for RIF. It has been shown that the infiltration of macrophages andT cells and lymphocyte dysfunction are two major mechanisms contributing toUUO-induced RIF model. In this model, at cellular level, tubular dilatation leads tubularepithelia lose their epithelial characteristics and acquire mesenchymal traits such as α-SMAexpression and actin reorganization. Therefore, tubular epithelial cells become the majorsource of renal myofibroblast during EMT process. At molecular level, TGF-β1plays a keyrole in EMT via activation of its downstream Rho/ROCK signaling pathway.
Recently, adenosine A_(2A) receptor (A_(2A)R) emerges as a novel inflammation regulatoraffecting on inflammation process and tissue repair. Pharmacology studies showed thatA_(2A)R agonist, CGS21680and ATL193, can effectively suppress inflammation. Activationof A_(2A)R leads to attenuation of glomerulonephritis and renal injury. Further, recent studyidentified that A_(2A)R activation inhibits Rho/ROCK1in hepatic stellate cells. All abovestrongly suggest that A_(2A)R manipulation plays an important regulatory role oninflammation on EMT event. Therefore, we hypothesize that activation of A_(2A)R maysuppress cellular infiltration, EMT event and profibrogenic factors, thereby to preventconsequent pathology of RIF. Conversely, inactivation of A_(2A)R may lead exacerbation ofRIF.
Using experimental UUO-induced RIF mouse model, we evaluated the modulatoryeffect of A_(2A)R-based manipulation on several aspects of RIF progression, includinginterstitial lymphocyte infiltration, cellular biomarkers of EMT, expression of profibrogenicfactor TGF-β1and its downstream Rho/ROCK1pathway, as well as the consequentextracellular matrix accumulation.
Methods
To test this hypothesis we applied unilateral ureteral obstruction (UUO) model of RIFon A_(2A)R knockout mice and their littermates, and combined the intervention of selectiveA_(2A)R agonist, CGS21680. At the day3,7and14post-RIF model establishment, weevaluated the effects of A_(2A)R manipulation on molecular pathological progress of RIF,including imunohistochemistry of collagen types I, III, α-SMA and CD4+T lymphocyte,CD4+CD25+FoxP3+regulatory T cells (Treg), Western blot of E-cadherin and α-smoothmuscle actin (α-SMA), and quantitative PCR for ROCK1and TGF-β1mRNAmeasurement.
Results
Our data showed that activation of A_(2A)R significantly suppressed the deposition ofcollagen types I, III, the infiltration of CD4+T lymphocytes as well as the expression ofTGF-β1and ROCK1that inhibited and postponed the process of EMT. Conversely, geneticinactivation of A_(2A)R exacerbated aforementioned pathophysiological processes of RIF.
Conclusion
Together, activation of A2AR effectively alleviated EMT and RIF in mice, suggestingA2AR as a potential therapeutic target for the treatment of RIF.
引文
1. Isaka Y, Takahara S, Imai E (2008) Chronic deteriorating renal function and renalfibrosis. Contrib Nephrol159:109-121.
2. Pannarale G, Carbone R, Del Mastro G, Gallo C, Gattullo V, et al.(2010) The agingkidney: structural changes. J Nephrol23Suppl15: S37-40.
3. Strutz F (2001) Potential methods to prevent interstitial fibrosis in renal disease. ExpertOpin Investig Drugs10:1989-2001.
4. Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol7:684-696.
5. Tan X, Li Y, Liu Y (2007) Therapeutic role and potential mechanisms of active VitaminD in renal interstitial fibrosis. J Steroid Biochem Mol Biol103:491-496.
6. Hao S, He W, Li Y, Ding H, Hou Y, et al.(2011) Targeted inhibition ofbeta-catenin/CBP signaling ameliorates renal interstitial fibrosis. J Am Soc Nephrol22:1642-1653.
7. Klahr S, Morrissey J (2002) Obstructive nephropathy and renal fibrosis. Am J PhysiolRenal Physiol283: F861-875.
8. Vaughan ED, Jr., Marion D, Poppas DP, Felsen D (2004) Pathophysiology of unilateralureteral obstruction: studies from Charlottesville to New York. J Urol172:2563-2569.
9. Harris RC, Neilson EG (2006) Toward a unified theory of renal progression. Annu RevMed57:365-380.
10. Tapmeier TT, Fearn A, Brown K, Chowdhury P, Sacks SH, et al.(2010) Pivotal role ofCD4+T cells in renal fibrosis following ureteric obstruction. Kidney Int78:351-362.
11. Tian YC, Fraser D, Attisano L, Phillips AO (2003) TGF-beta1-mediated alterations ofrenal proximal tubular epithelial cell phenotype. Am J Physiol Renal Physiol285:F130-142.
12. Mucsi I, Rosivall L (2007) Epithelial-mesenchymal transition in renal tubular cells inthe pathogenesis of progressive tubulo-interstitial fibrosis. Acta Physiol Hung94:117-131.
13. Garcia GE, Truong LD, Li P, Zhang P, Du J, et al.(2008) Adenosine A2A receptoractivation and macrophage-mediated experimental glomerulonephritis. FASEB J22:445-454.
14. Mazzon E, Esposito E, Impellizzeri D, R DIP, Melani A, et al.(2011) CGS21680, anagonist of the adenosine (A2A) receptor, reduces progression of murine type IIcollagen-induced arthritis. J Rheumatol38:2119-2129.
15. Impellizzeri D, Di Paola R, Esposito E, Mazzon E, Paterniti I, et al.(2011) CGS21680,an agonist of the adenosine (A2A) receptor, decreases acute lung inflammation. Eur JPharmacol668:305-316.
16. Ferenbach DA, Hughes J (2011) Adenosine A(2A) agonists as therapy forglomerulonephritis. Kidney Int80:329-331.
17. Garcia GE, Truong LD, Chen JF, Johnson RJ, Feng L (2011) Adenosine A(2A) receptoractivation prevents progressive kidney fibrosis in a model of immune-associatedchronic inflammation. Kidney Int80:378-388.
18. Zhang L, Yang N, Wang S, Huang B, Li F, et al.(2011) Adenosine2A receptor isprotective against renal injury in MRL/lpr mice. Lupus20:667-677.
19. Sohail MA, Hashmi AZ, Hakim W, Watanabe A, Zipprich A, et al.(2009) Adenosineinduces loss of actin stress fibers and inhibits contraction in hepatic stellate cells viaRho inhibition. Hepatology49:185-194.
1. Hostetter TH, Olson JL, Rennke HG et al. Hyperfiltration in remnant nephrons: apotentially adverse response to renal ablation. Am J Physiol1981;241: F85–F93.
2. Ma LJ, Fogo AB. Model of robust induction of glomerulosclerosis in mice: Importanceof genetic background. Kidney Int2003;64:350–355.
3. Schnaper HW, Kopp JB. Why kidneys fail: Report from an American Society ofNephrology Advances in Research Conference. J Am Soc Nephol2006;17:1777–1781.
4. Schainuck LI, Striker GE, Cutler RE et al. Structural-functional correlations in renaldisease. Part II: The correlations. Hum Pathol1970;1:631–641.
5. Nagle RB, Bulger RE, Cutler RE et al. Unilateral obstructive nephropathy in therabbit:I. Early morphologic, physiologic, and histochemical changes. Lab Invest1973;28:456–467.
6. Sharma AK, Mauer SM, Kim Y et al. Interstitial fibrosis in obstructive nephropathy.Kidney Int1993;44:774–788.
7. Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis. Am J Physiol2002;283:F861–F875.
8. Eddy AA. Can renal fibrosis be reversed? Pediatr Nephrol2005;20:1369–1375.
9. Chevalier RL. Counterbalance in functional adaptation to ureteral obstruction duringdevelopment. Pediatr Nephrol1990;4:442–444.
10. Hironaka K, Sakaida I, Uchida K et al. Correlation between stellate cell activation andserum fibrosis markers in choline-deficient L-amino acid-defined diet-induced rat liverfibrosis. Dig Dis Sci2000;45:1935–1943.
11. Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol2000;15:290–301.
12. Kriz W, LeHir M. Pathways to nephron loss starting from glomerular diseases–Insightsfrom animal models. Kidney Int2005;67:404–419.
13. Tashiro K, Tamada S, Kuwabara N et al. Attenuation of renal fibrosis by proteasomeinhibition in rat obstructive nephropathy: possible role of nuclear factor kappaB. Int JMol Med2003;12:587–592.
14. Miyajima A, Kosaka T, Seta K et al. Novel nuclear factor kappaB activation inhibitorprevents inflammatory injury in unilateral ureteral obstruction. J Urol2003;169:1559–1563.
15. Iwano M, Plieth D, Danoff TM et al. Evidence that fibroblasts derive from epitheliumduring tissue fibrosis. J Clin Invest2002;110:341–350.
16. Zeisberg EM, Potenta SE, Sugimoto H et al. Fibroblasts in kidney fibrosis emerge viaendothelial-to-mesenchymal transition. J Am Soc Nephrol2008;19:2282–2287.
17. Ohashi R, Shimizu A, Masuda Y et al. Peritubular capillary regression during theprogression of experimental obstructive nephropathy. J Am Soc Nephrol2002;13:1795–1805.
18. Lin SL, Kisseleva T, Brenner DA et al. Pericytes and perivascular fibroblasts are theprimary source of collagen-producing cells in obstructive fibrosis of the kidney. Am JPathol2008;173:1617–1627.
19. Bascands JL, Schanstra JP. Obstructive nephropathy: insights from geneticallyengineered animals. Kidney Int2005;68:925–937.
20. Chevalier RL. Obstructive nephropathy: towards biomarker discovery and gene therapy.Nat Clin Prac Nephrol2006;2:157–168.
21. Chevalier RL, Cachat F. Role of angiotensin II in chronic ureteral obstruction. In: WolfG (ed). The Renin-Angiotensin System and Progression of Renal Diseases.1ed.Karger: Basel,2001pp250–260.
22. Pittock ST, Norby SM, Grande JP et al. MCP-1is up-regulated in unstressed andstressed HO-1knockout mice: Pathophysiologic correlates. Kidney Int2005;68:611–622.
23. Miyajima A, Chen J, Lawrence C et al. Antibody to transforming growth factor-bameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int2000;58:2301–2313.
24. Morrissey J, Hurska K, Guo G et al. Bone morphogenetic protein-7improves renalfibrosis and accelerates the return of renal function. J Am Soc Nephrol2002;13:S14–S21.
25. Zhang G, Kim H, Cai X et al. Urokinase receptor deficiency accelerates renal fibrosis inobstructive nephropathy. J Am Soc Nephrol2005;14:1254–1271.
26. Docherty NG, O’Sullivan OE, Healy DA et al. Evidence that inhibition of tubular cellapoptosis protects against renal damage and development of fibrosis following uretericobstruction. Am J Physiol Renal Physiol2006;290: F4–F13, Jan.F4-13,/1.
27. Morrissey JJ, Klahr S. Effect of AT2receptor blockade on the pathogenesis of renalfibrosis. Am J Physiol Renal Physiol1999;276: F39–F45.
28. Duffield JS. The inflammatory macrophage: a story of Jekyll and Hyde. Clin Sci2003;104:27–38.
29. Eardley KS, Cockwell P. Macrophages and progressive tubulointerstitial disease.Kidney Int2005;68:437–455.
30. Chevalier RL. Pathogenesis of renal injury in obstructive uropathy. Curr Opin Pediatr2006;18:153–160.
31. Yoo KH, Thornhill BA, Forbes MS et al. Osteopontin regulates renal apoptosis andinterstitial fibrosis in neonatal chronic unilateral ureteral obstruction. Kidney Int2006;70:1735–1741.
32. Rouschop KMA, Sewnath ME, Claessen N et al. CD44deficiency increases tubulardamage but reduces renal fibrosis in obstructive nephropathy. J Am Soc Nephrol2004;15:674–686.
33. Yukawa K, Hoshino K, Kishino M et al. Deletion of the kinase domain indeath-associated protein kinase attenuates renal tubular cell apoptosis in chronicobstructive uropathy. Int J Mol Med2004;13:515–520.
1. Isaka Y, Takahara S, Imai E. Chronic deteriorating renal function and renal fibrosis.Contrib Nephrol2008,159:109-121.
2. Pannarale G, Carbone R, Del Mastro G, Gallo C, Gattullo V, Natalicchio L, et al. Theaging kidney: structural changes. J Nephrol2010,23Suppl15:S37-40.
3. Chevalier RL. Molecular and cellular pathophysiology of obstructive nephropathy.Pediatr Nephrol1999,13:612-619.
4. Vielhauer V, Allam R, Lindenmeyer MT, Cohen CD, Draganovici D, Mandelbaum J, etal. Efficient renal recruitment of macrophages and T cells in mice lacking the duffyantigen/receptor for chemokines. Am J Pathol2009,175:119-131.
5. Lian YG, Zhou QG, Zhang YJ, Zheng FL. VEGF ameliorates tubulointerstitial fibrosisin unilateral ureteral obstruction mice via inhibition of epithelial-mesenchymaltransition. Acta Pharmacol Sin2011,32:1513-1521.
6. Nasu T, Kinomura M, Tanabe K, Yamasaki H, Htay SL, Saito D, et al. Asustained-release prostacyclin analog ONO-1301ameliorates tubulointerstitialalterations in a mouse obstructive nephropathy model. Am J Physiol Renal Physiol2012.
7. Omori H, Kawada N, Inoue K, Ueda Y, Yamamoto R, Matsui I, et al. Use of xanthineoxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis inunilateral ureteral obstructive nephropathy. Clin Exp Nephrol2012.
8. Guerrot D, Kerroch M, Placier S, Vandermeersch S, Trivin C, Mael-Ainin M, et al.Discoidin domain receptor1is a major mediator of inflammation and fibrosis inobstructive nephropathy. Am J Pathol2011,179:83-91.
9. Fernandez P, Trzaska S, Wilder T, Chiriboga L, Blackburn MR, Cronstein BN, et al.Pharmacological blockade of A2A receptors prevents dermal fibrosis in a model ofelevated tissue adenosine. Am J Pathol2008,172:1675-1682.
10. Chan ES, Montesinos MC, Fernandez P, Desai A, Delano DL, Yee H, et al. AdenosineA(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol2006,148:1144-1155.
11. Garcia GE, Truong LD, Chen JF, Johnson RJ, Feng L. Adenosine A(2A) receptoractivation prevents progressive kidney fibrosis in a model of immune-associatedchronic inflammation. Kidney Int2011,80:378-388.
12. Chen JF, Huang Z, Ma J, Zhu J, Moratalla R, Standaert D, et al. A(2A) adenosinereceptor deficiency attenuates brain injury induced by transient focal ischemia in mice.J Neurosci1999,19:9192-9200.
13. Moriyama T, Kawada N, Ando A, Yamauchi A, Horio M, Nagata K, et al.Up-regulation of HSP47in the mouse kidneys with unilateral ureteral obstruction.Kidney Int1998,54:110-119.
14. Luo L, Sun Z, Wu W, Luo G. Mycophenolate mofetil and FK506have different effectson kidney allograft fibrosis in rats that underwent chronic allograft nephropathy. BMCNephrol2012,13:53.
15. Iwano M. EMT and TGF-beta in renal fibrosis. Front Biosci (Schol Ed)2010,2:229-238.
16. Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol2010,21:1819-1834.
17. Rebola N, Simoes AP, Canas PM, Tome AR, Andrade GM, Barry CE, et al. AdenosineA2A receptors control neuroinflammation and consequent hippocampal neuronaldysfunction. J Neurochem2011,117:100-111.
18. Scheibner KA, Boodoo S, Collins S, Black KE, Chan-Li Y, Zarek P, et al. Theadenosine a2a receptor inhibits matrix-induced inflammation in a novel fashion. Am JRespir Cell Mol Biol2009,40:251-259.
19. Warren CA, Calabrese GM, Li Y, Pawlowski SW, Figler RA, Rieger J, et al. Effects ofadenosine A(2)A receptor activation and alanyl-glutamine in Clostridium difficiletoxin-induced ileitis in rabbits and cecitis in mice. BMC Infect Dis2012,12:13.
20. Lukashev D, Ohta A, Apasov S, Chen JF, Sitkovsky M. Cutting edge: Physiologicattenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosinereceptor in vivo. J Immunol2004,173:21-24.
21. Sitkovsky M, Lukashev D, Deaglio S, Dwyer K, Robson SC, Ohta A. Adenosine A2Areceptor antagonists: blockade of adenosinergic effects and T regulatory cells. Br JPharmacol2008,153Suppl1:S457-464.
22. Heinrich EL, Walser TC, Krysan K, Liclican EL, Grant JL, Rodriguez NL, et al. Theinflammatory tumor microenvironment, epithelial mesenchymal transition and lungcarcinogenesis. Cancer Microenviron2012,5:5-18.
23. Meng LQ, Tang JW, Wang Y, Zhao JR, Shang MY, Zhang M, et al. Astragaloside IVsynergizes with ferulic acid to inhibit renal tubulointerstitial fibrosis in rats withobstructive nephropathy. Br J Pharmacol2011,162:1805-1818.
24. Burns WC, Kantharidis P, Thomas MC. The role of tubular epithelial-mesenchymaltransition in progressive kidney disease. Cells Tissues Organs2007,185:222-231.
25. Mucsi I, Rosivall L. Epithelial-mesenchymal transition in renal tubular cells in thepathogenesis of progressive tubulo-interstitial fibrosis. Acta Physiol Hung2007,94:117-131.
26. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, et al.Transforming growth factor-beta1mediates epithelial to mesenchymal transdifferentiationthrough a RhoA-dependent mechanism. Mol Biol Cell2001,12:27-36.
27. Sohail MA, Hashmi AZ, Hakim W, Watanabe A, Zipprich A, Groszmann RJ, et al.Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellatecells via Rho inhibition. Hepatology2009,49:185-194.
1. Isaka Y, Takahara S, Imai E (2008) Chronic deteriorating renal function and renalfibrosis. Contrib Nephrol159:109-121.
2. Pannarale G, Carbone R, Del Mastro G, Gallo C, Gattullo V, et al.(2010) The agingkidney: structural changes. J Nephrol23Suppl15: S37-40.
3. Strutz F (2001) Potential methods to prevent interstitial fibrosis in renal disease. ExpertOpin Investig Drugs10:1989-2001.
4. Mucsi I, Rosivall L (2007) Epithelial-mesenchymal transition in renal tubular cells inthe pathogenesis of progressive tubulo-interstitial fibrosis. Acta Physiol Hung94:117-131.
5. Tan X, Li Y, Liu Y (2007) Therapeutic role and potential mechanisms of active VitaminD in renal interstitial fibrosis. J Steroid Biochem Mol Biol103:491-496.
6. Hao S, He W, Li Y, Ding H, Hou Y, et al.(2011) Targeted inhibition of beta-catenin/CBPsignaling ameliorates renal interstitial fibrosis. J Am Soc Nephrol22:1642-1653.
7. Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol7:684-696.
8. Iwano M (2010) EMT and TGF-beta in renal fibrosis. Front Biosci (Schol Ed)2:229-238.
9. Zeisberg M, Neilson EG (2010) Mechanisms of tubulointerstitial fibrosis. J Am SocNephrol21:1819-1834.
10. Klahr S, Morrissey J (2002) Obstructive nephropathy and renal fibrosis. Am J PhysiolRenal Physiol283: F861-875.
11. Vaughan ED, Jr., Marion D, Poppas DP, Felsen D (2004) Pathophysiology of unilateralureteral obstruction: studies from Charlottesville to New York. J Urol172:2563-2569.
12. Harris RC, Neilson EG (2006) Toward a unified theory of renal progression. Annu RevMed57:365-380.
13. Tapmeier TT, Fearn A, Brown K, Chowdhury P, Sacks SH, et al.(2010) Pivotal role ofCD4+T cells in renal fibrosis following ureteric obstruction. Kidney Int78:351-362.
14. Tian YC, Fraser D, Attisano L, Phillips AO (2003) TGF-beta1-mediated alterations ofrenal proximal tubular epithelial cell phenotype. Am J Physiol Renal Physiol285:F130-142.
15. Mazzon E, Esposito E, Impellizzeri D, R DIP, Melani A, et al.(2011) CGS21680, anagonist of the adenosine (A2A) receptor, reduces progression of murine type IIcollagen-induced arthritis. J Rheumatol38:2119-2129.
16. Impellizzeri D, Di Paola R, Esposito E, Mazzon E, Paterniti I, et al.(2011) CGS21680,an agonist of the adenosine (A2A) receptor, decreases acute lung inflammation. Eur JPharmacol668:305-316.
17. Ferenbach DA, Hughes J (2011) Adenosine A(2A) agonists as therapy for glomerulonephritis.Kidney Int80:329-331.
18. Garcia GE, Truong LD, Chen JF, Johnson RJ, Feng L (2011) Adenosine A(2A) receptoractivation prevents progressive kidney fibrosis in a model of immune-associatedchronic inflammation. Kidney Int80:378-388.
19. Zhang L, Yang N, Wang S, Huang B, Li F, et al.(2011) Adenosine2A receptor isprotective against renal injury in MRL/lpr mice. Lupus20:667-677.
20. Sohail MA, Hashmi AZ, Hakim W, Watanabe A, Zipprich A, et al.(2009) Adenosineinduces loss of actin stress fibers and inhibits contraction in hepatic stellate cells viaRho inhibition. Hepatology49:185-194.
21. Chen JF, Huang Z, Ma J, Zhu J, Moratalla R, et al.(1999) A(2A) adenosine receptordeficiency attenuates brain injury induced by transient focal ischemia in mice. JNeurosci19:9192-9200.
22. Mao H, Li Z, Zhou Y, Zhuang S, An X, et al.(2008) HSP72attenuates renal tubular cellapoptosis and interstitial fibrosis in obstructive nephropathy. Am J Physiol RenalPhysiol295: F202-214.
23. Wu G, Tu Y, Jia R (2010) The influence of fasudil on the epithelial-mesenchymaltransdifferentiation of renal tubular epithelial cells from diabetic rats. BiomedPharmacother64:124-129.
24. Zheng G, Wang Y, Mahajan D, Qin X, Alexander SI, et al.(2005) The role oftubulointerstitial inflammation. Kidney Int Suppl: S96-100.
25. Tipping PG, Holdsworth SR (2006) T cells in crescentic glomerulonephritis. J Am SocNephrol17:1253-1263.
26. Strutz F, Neilson EG (1994) The role of lymphocytes in the progression of interstitialdisease. Kidney Int Suppl45: S106-110.
27. Yang N, Isbel NM, Nikolic-Paterson DJ, Li Y, Ye R, et al.(1998) Local macrophageproliferation in human glomerulonephritis. Kidney Int54:143-151.
28. Robertson H, Ali S, McDonnell BJ, Burt AD, Kirby JA (2004) Chronic renal allograftdysfunction: the role of T cell-mediated tubular epithelial to mesenchymal celltransition. J Am Soc Nephrol15:390-397.
29. Vielhauer V, Anders HJ, Mack M, Cihak J, Strutz F, et al.(2001) Obstructivenephropathy in the mouse: progressive fibrosis correlates with tubulointerstitialchemokine expression and accumulation of CC chemokine receptor2-and5-positiveleukocytes. J Am Soc Nephrol12:1173-1187.
30. Eis V, Luckow B, Vielhauer V, Siveke JT, Linde Y, et al.(2004) Chemokine receptorCCR1but not CCR5mediates leukocyte recruitment and subsequent renal fibrosis afterunilateral ureteral obstruction. J Am Soc Nephrol15:337-347.
31. Kitagawa K, Wada T, Furuichi K, Hashimoto H, Ishiwata Y, et al.(2004) Blockade ofCCR2ameliorates progressive fibrosis in kidney. Am J Pathol165:237-246.
32. Anders HJ, Vielhauer V, Frink M, Linde Y, Cohen CD, et al.(2002) A chemokinereceptor CCR-1antagonist reduces renal fibrosis after unilateral ureter ligation. J ClinInvest109:251-259.
33. Lukashev D, Ohta A, Apasov S, Chen JF, Sitkovsky M (2004) Cutting edge: Physiologicattenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosinereceptor in vivo. J Immunol173:21-24.
34. Sitkovsky M, Lukashev D, Deaglio S, Dwyer K, Robson SC, et al.(2008) AdenosineA2A receptor antagonists: blockade of adenosinergic effects and T regulatory cells. Br JPharmacol153Suppl1: S457-464.
35. Pozdzik AA, Salmon IJ, Husson CP, Decaestecker C, Rogier E, et al.(2008) Patterns ofinterstitial inflammation during the evolution of renal injury in experimentalaristolochic acid nephropathy. Nephrol Dial Transplant23:2480-2491.
36. Tang TT, Yuan J, Zhu ZF, Zhang WC, Xiao H, et al.(2012) Regulatory T cellsameliorate cardiac remodeling after myocardial infarction. Basic Res Cardiol107:232.
37. Ohta A, Kini R, Subramanian M, Madasu M, Sitkovsky M (2012) The development andimmunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells areunder influence of the adenosine-A2A adenosine receptor pathway. Front Immunol3:190.
38. Zhou B, Buckley ST, Patel V, Liu Y, Luo J, et al.(2012) Troglitazone attenuatesTGF-beta1-induced EMT in alveolar epithelial cells via a PPARgamma-independentmechanism. PLoS One7: e38827.
39. Masszi A, Di Ciano C, Sirokmany G, Arthur WT, Rotstein OD, et al.(2003) Central rolefor Rho in TGF-beta1-induced alpha-smooth muscle actin expression duringepithelial-mesenchymal transition. Am J Physiol Renal Physiol284: F911-924.
40. Prakash J, de Borst MH, Lacombe M, Opdam F, Klok PA, et al.(2008) Inhibition ofrenal rho kinase attenuates ischemia/reperfusion-induced injury. J Am Soc Nephrol19:2086-2097.
41. Kalaji R, Wheeler AP, Erasmus JC, Lee SY, Endres RG, et al.(2012) ROCK1andROCK2regulate epithelial polarisation and geometric cell shape. Biol Cell.
42. Baum B, Georgiou M (2011) Dynamics of adherens junctions in epithelial establishment,maintenance, and remodeling. J Cell Biol192:907-917.
43. Otsu K, Kishigami R, Fujiwara N, Ishizeki K, Harada H (2011) Functional role ofRho-kinase in ameloblast differentiation. J Cell Physiol226:2527-2534.
44. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, et al.(2001) Transforminggrowth factor-beta1mediates epithelial to mesenchymal transdifferentiation through aRhoA-dependent mechanism. Mol Biol Cell12:27-36.
45. Fu P, Liu F, Su S, Wang W, Huang XR, et al.(2006) Signaling mechanism of renalfibrosis in unilateral ureteral obstructive kidney disease in ROCK1knockout mice. JAm Soc Nephrol17:3105-3114.
1. Hewitson TD. Renal tubulointerstitial fibrosis: common but never simple. Am J PhysiolRenal Physiol2009;296: F1239–F1244.
2. Tipping PG, Kitching AR. Glomerulonephritis, Th1and Th2: what’s new? Clin ExpImmunol2005;142:207–215.
3. Strutz F, Neilson EG. The role of lymphocytes in the progression of interstitial disease.Kidney Int Suppl1994;45: S106–S110.
4. Yang N, Isbel NM, Nikolic-Paterson DJ et al.Local macrophage proliferation in humanglomerulonephritis. Kidney Int1998;54:143–151.
5. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol2008;214:199–210.
6. Shappell SB, Gurpinar T, Lechago J et al. Chronic obstructive uropathy in severecombined immunodeficient (SCID) mice: lymphocyte infiltration is not required forprogressive tubulointerstitial injury. J Am Soc Nephrol1998;9:1008–1017.
7. Niedermeier M, Reich B, Rodriguez Gomez M et al. CD4+T cells control thedifferentiation of Gr1+monocytes into fibrocytes. Proc Natl Acad Sci USA2009;106:17892–17897.
8. Lin SL, Kisseleva T, Brenner DA e t al. Pericytes and perivascular fibroblasts are theprimary source ofcollagen-producing cells in obstructive fibrosis of the kidney. A m JPathol2008;173:1617–1627.
9. Roufosse C, Bou-Gharios G, Prodromidi E e t al. Bone marrow-derived cells do notcontribute significantly to collagen I synthesis in a murine model of renal fibrosis. J AmSoc Nephrol2006;17:775–782.
10. Tapmeier TT, Fearn A, Brown K et al. Pivotal role of CD4+T cells in renal fibrosisfollowing ureteric obstruction. K idney Int2010;78:351–362.
11. Henderson NC, Mackinnon AC, Farnworth SL et al. Galectin-3expression andsecretion links macrophages to the promotion of renal fibrosis. Am J Pathol2008;172:288–298.
12. Ma F, Liu J, Kitching AR e t al. Targeting renal macrophage accumulation throughinhibition of c-fms kinase activity reduces tubular apoptosis but fails to modifyprogressive fibrosis in the obstructed kidney. A m J Physiol Renal Physiol2009;296:F177–F185.
13. Isaka Y, Tsujie M, Ando Y e t al. Transforming growth factor-beta1antisenseoligodeoxynucleotidesblock interstitial fibrosis in unilateral ureteral obstruction.Kidney Int2000;58:1885–1892.
14. Humphreys BD, Lin SL, Kobayashi A e t al. Fate tracing reveals the pericyte and notepithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol2010;176:85–97.
1. Coresh, J. et al. Prevalence of chronic kidney disease in the United States. JAMA298,2038–2047(2007).
2. United States Renal Data System. Annual Data Report2009[online], http://www.usrds.org/adr.htm (2010).
3. Sharma, S. K. et al. Burden of CKD, proteinuria, and cardiovascular risk amongChinese, Mongolian, and Nepalese participants in the International Society ofNephrology screening programs. Am. J. Kidney Dis.56,915–927(2010).
4. Zhang, L. et al. Prevalence and factors associated with CKD: a population studyfrom Beijing. Am. J. Kidney Dis.51,373–384(2008).
5. Liu, Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. KidneyInt.69,213–217(2006).
6. Wynn, T. A. Cellular and molecular mechanisms of fibrosis. J. Pathol.214,199–210(2008).
7. Zeisberg, M.&Neilson, E. G. Mechanisms of tubulointerstitial fibrosis. J. Am. Soc.Nephrol.21,1819–1834(2010).
8. Boor, P., Ostendorf, T.&Floege, J. Renal fibrosis: novel insights into mechanismsand therapeutic targets. Nat. Rev. Nephrol.6,643–656(2010).
9. Li, Y. et al. Epithelial-to-mesenchymal transition is a potential pathway leading topodocyte dysfunction and proteinuria. Am. J. Pathol.172,299–308(2008).
10. Yamaguchi, Y. et al. Epithelial-mesenchymal transition as an explanation forpodocyte depletion in diabetic nephropathy. Am. J. Kidney Dis.54,653–664(2009).
11. Kang, Y. S. et al. Inhibition of integrin-linked kinase blocks podocyte epithelial-mesenchymal transition and ameliorates proteinuria. Kidney Int.78,363–373(2010).
12. Eddy, A. A. Molecular basis of renal fibrosis. Pediatr. Nephrol.15,290–301(2000).
13. Chung, A. C.&Lan, H. Y. Chemokines in renal injury. J. Am. Soc. Nephrol.22,802–809(2011).
14. Schroder, K.&Tschopp, J. The inflammasomes. Cell140,821–832(2010).
15. Nathan, C.&Ding, A. Nonresolving inflammation. Cell140,871–882(2010).
16. Vielhauer, V., Kulkarni, O., Reichel, C. A.&Anders, H. J. Targeting the recruitmentof monocytes and macrophages in renal disease. Semin. Nephrol.30,318–333(2010).
17. Vernon, M. A., Mylonas, K. J.&Hughes, J. Macrophages and renal fibrosis. Semin.Nephrol.30,302–317(2010).
18. Duffield, J. S. Macrophages and immunologic inflammation of the kidney. Semin.Nephrol.30,234–254(2010).
19. Ricardo, S. D., van Goor, H.&Eddy, A. A. Macrophage diversity in renal injury andrepair. J. Clin. Invest.118,3522–3530(2008).
20. Wang, Y.&Harris, D. C. Macrophages in renal disease. J. Am. Soc. Nephrol.22,21–27(2011).
21. Grande, M. T., Pérez-Barriocanal, F.&López-Novoa, J. M. Role of inflammation intubulo-interstitial damage associated to obstructive nephropathy. J. Inflamm.7,19(2010).
22. Tapmeier, T. T. et al. Pivotal role of CD4+T cells in renal fibrosis following uretericobstruction. Kidney Int.78,351–362(2010).
23. Lin, S. L., Casta o, A. P., Nowlin, B. T., Lupher, M. L. Jr&Duffield, J. S. Bonemarrow Ly6Chigh monocytes are selectively recruited to injured kidney anddifferentiate into functionally distinct populations. J. Immunol.183,6733–6743(2009).
24. Henderson, N. C. et al. Galectin-3expression and secretion links macrophages to thepromotion of renal fibrosis. Am. J. Pathol.172,288–298(2008).
25. Ko, G. J., Boo, C. S., Jo, S. K., Cho, W. Y.&Kim, H. K. Macrophages contribute tothe development of renal fibrosis following ischaemia/reperfusion-induced acutekidney injury. Nephrol. Dial. Transplant.23,842–852(2008).
26. Wang, Y. et al. By homing to the kidney, activated macrophages potently exacerbaterenal injury. Am. J. Pathol.172,1491–1499(2008).
27. Kaissling, B.&Le Hir, M. The renal cortical interstitium: morphological andfunctional aspects. Histochem. Cell Biol.130,247–262(2008).
28. John, R.&Nelson, P. J. Dendritic cells in the kidney. J. Am. Soc. Nephrol.18,2628–2635(2007).
29. Teteris, S. A., Engel, D. R.&Kurts, C. Homeostatic and pathogenic role of renaldendritic cells. Kidney Int.80,139–145(2011).
30. Macconi, D. et al. Proteasomal processing of albumin by renal dendritic cellsgenerates antigenic peptides. J. Am. Soc. Nephrol.20,123–130(2009).
31. Heymann, F. et al. Kidney dendritic cell activation is required for progression ofrenal disease in a mouse model of glomerular injury. J. Clin. Invest.119,1286–1297(2009).
32. Hochheiser, K. et al. Kidney dendritic cells become pathogenic during crescenticglomerulonephritis with proteinuria. J. Am. Soc. Nephrol.22,306–316(2011).
33. Timoshanko, J. R., Kitching, A. R., Semple, T. J., Tipping, P. G.&Holdsworth, S. R.A pathogenetic role for mast cells in experimental crescentic glomerulonephritis. J.Am. Soc. Nephrol.17,150–159(2006).
34. Holdsworth, S. R.&Summers, S. A. Role of mast cells in progressive renal diseases.J. Am. Soc. Nephrol.19,2254–2261(2008).
35. Kanamaru, Y. et al. Mast cell-mediated remodeling and fibrinolytic activity protectagainst fatal glomerulonephritis. J. Immunol.176,5607–5615(2006).
36. Anders, H. J. et al. A chemokine receptor CCR-1antagonist reduces renal fibrosisafter unilateral ureter ligation. J. Clin. Invest.109,251–259(2002).
37. Sayyed, S. G. et al. An orally active chemokine receptor CCR2antagonist preventsglomerulosclerosis and renal failure in type2diabetes. Kidney Int.80,68–78(2011).
38. Tan, X., Wen, X.&Liu, Y. Paricalcitol inhibits renal inflammation by promotingvitamin D receptor-mediated sequestration of NF-κB signaling. J. Am. Soc. Nephrol.19,1741–1752(2008).
39. Wen, X., Li, Y.&Liu, Y. Opposite action of peroxisome proliferator-activatedreceptor-γ in regulating renal inflammation: functional switch by its ligand. J. Biol.Chem.285,29981–29988(2010).
40. Kawai, T. et al. PPAR-γ agonist attenuates renal interstitial fibrosis andinflammation through reduction of TGF-β. Lab. Invest.89,47–58(2009).
41. Khan, S. B. et al. Antibody blockade of TNF-α reduces inflammation and scarring inexperimental crescentic glomerulonephritis. Kidney Int.67,1812–1820(2005).
42. Giannopoulou, M. et al. Hepatocyte growth factor exerts its anti-inflammatoryaction by disrupting nuclear factor-κB signaling. Am. J. Pathol.173,30–41(2008).
43. Gong, R., Rifai, A.&Dworkin, L. D. Anti-inflammatory effect of hepatocyte growthfactor in chronic kidney disease: targeting the inflamed vascular endothelium. J. Am.Soc. Nephrol.17,2464–2473(2006).
44. Jones, L. K. et al. IL-1RI deficiency ameliorates early experimental renal interstitialfibrosis. Nephrol. Dial. Transplant.24,3024–3032(2009).
45. Yu, C., Gong, R., Rifai, A., Tolbert, E. M.&Dworkin, L. D. Long-term, high-dosagecandesartan suppresses inflammation and injury in chronic kidney disease:nonhemodynamic renal protection. J. Am. Soc. Nephrol.18,750–759(2007).
46. Pate, M., Damarla, V., Chi, D. S., Negi, S.&Krishnaswamy, G. Endothelial cellbiology: role in the inflammatory response. Adv. Clin. Chem.52,109–130(2010).
47. López-Novoa, J. M.&Nieto, M. A. Inflammation and EMT: an alliance towardsorgan fibrosis and cancer progression. EMBO Mol. Med.1,303–314(2009).
48. Nightingale, J. et al. Oncostatin M, a cytokine released by activated mononuclearcells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathwayactivation. J. Am. Soc. Nephrol.15,21–32(2004).
49. Li, Q. et al. Monocytes induce proximal tubular epithelial mesenchymal transitionthrough NF-κB dependent upregulation of ICAM-1. J. Cell. Biochem.112,1585–1592(2011).
50. Wu, Y. et al. Stabilization of snail by NF-κB is required for inflammation-inducedcell migration and invasion. Cancer Cell15,416–428(2009).
51. Boutet, A. et al. Snail activation disrupts tissue homeostasis and induces fibrosis inthe adult kidney. EMBO J.25,5603–5613(2006).
52. Rowe, R. G. et al. Mesenchymal cells reactivate Snail1expression to drivethree-dimensional invasion programs. J. Cell Biol.184,399–408(2009).
53. Thiery, J. P., Acloque, H., Huang, R. Y.&Nieto, M. A. Epithelial-mesenchymaltransitions in development and disease. Cell139,871–890(2009).
54. Inoue, T. et al. Fibroblast expression of an IκB dominant-negative transgeneattenuates renal fibrosis. J. Am. Soc. Nephrol.21,2047–2052(2010).
55. Li, Y., Yang, J., Luo, J. H., Dedhar, S.&Liu, Y. Tubular epithelial celldedifferentiation is driven by the helix-loop-helix transcriptional inhibitor Id1. J. Am.Soc. Nephrol.18,449–460(2007).
56. Yang, Y., Liou, H. C.&Sun, X. H. Id1potentiates NF-κB activation upon T cellreceptor signaling. J. Biol. Chem.281,34989–34996(2006).
57. Lin, J. et al. Inhibitor of differentiation1contributes to head and neck squamous cellcarcinoma survival via the NF-κB/survivin and phosphoinositide3-kinase/Aktsignaling pathways. Clin. Cancer Res.16,77–87(2010).
58. Duffield, J. S. Macrophages in kidney repair and regeneration. J. Am. Soc. Nephrol.22,199–201(2011).
59. Gandolfo, M. T. et al. Foxp3+regulatory T cells participate in repair of ischemicacute kidney injury. Kidney Int.76,717–729(2009).
60. Cao, Q. et al. IL-10/TGF-β-modified macrophages induce regulatory T cells andprotect against adriamycin nephrosis. J. Am. Soc. Nephrol.21,933–942(2010).
61. Meran, S.&Steadman, R. Fibroblasts and myofibroblasts in renal fibrosis. Int. J.Exp. Pathol.92,158–167(2011).
62. Grande, M. T.&López-Novoa, J. M. Fibroblast activation and myofibroblastgeneration in obstructive nephropathy. Nat. Rev. Nephrol.5,319–328(2009).
63. Schrimpf, C.&Duffield, J. S. Mechanisms of fibrosis: the role of the pericyte. Curr.Opin. Nephrol. Hypertens.20,297–305(2011).
64. Barnes, J. L.&Gorin, Y. Myofibroblast differentiation during fibrosis: role ofNAD(P)H oxidases. Kidney Int.79,944–956(2011).
65. Hewitson, T. D. Renal tubulointerstitial fibrosis: common but never simple. Am. J.Physiol. Renal Physiol.296, F1239–F1244(2009).
66. Strutz, F.&Zeisberg, M. Renal fibroblasts and myofibroblasts in chronic kidneydisease. J. Am. Soc. Nephrol.17,2992–2998(2006).
67. Paliege, A. et al. Hypoxia-inducible factor-2α-expressing interstitial fibroblasts arethe only renal cells that express erythropoietin under hypoxia-inducible factorstabilization. Kidney Int.77,312–318(2010).
68. Boor, P.&Floege, J. Chronic kidney disease growth factors in renal fibrosis. Clin.Exp. Pharmacol. Physiol.38,391–400(2011).
69. Floege, J., Eitner, F.&Alpers, C. E. A new look at platelet-derived growth factor inrenal disease. J. Am. Soc. Nephrol.19,12–23(2008).
70. Boye, K.&Maelandsmo, G. M. S100A4and metastasis: a small actor playing manyroles. Am. J. Pathol.176,528–535(2010).
71. Grigorian, M., Ambartsumian, N.&Lukanidin, E. Metastasis-inducing S100A4protein: implication in non-malignant human pathologies. Curr. Mol. Med.8,492–496(2008).
72. Wynn, T. A. Common and unique mechanisms regulate fibrosis in variousfibroproliferative diseases. J. Clin. Invest.117,524–529(2007).
73. Hinz, B. et al. The myofibroblast: one function, multiple origins. Am. J. Pathol.170,1807–1816(2007).
74. Lin, S. L., Kisseleva, T., Brenner, D. A.&Duffield, J. S. Pericytes and perivascularfibroblasts are the primary source of collagen-producing cells in obstructive fibrosisof the kidney. Am. J. Pathol.173,1617–1627(2008).
75. Takeji, M. et al. Smooth muscle α-actin deficiency in myofibroblasts leads toenhanced renal tissue fibrosis. J. Biol. Chem.281,40193–40200(2006).
76. Zou, J. et al. Upregulation of nestin, vimentin, and desmin in rat podocytes inresponse to injury. Virchows Arch.448,485–492(2006).
77. Phanish, M. K., Winn, S. K.&Dockrell, M. E. Connective tissue growthfactor-(CTGF, CCN2)—a marker, mediator and therapeutic target for renal fibrosis.Nephron Exp. Nephrol.114, e83–e92(2010).
78. B ttinger, E. P. TGF-β in renal injury and disease. Semin. Nephrol.27,309–320(2007).
79. Strutz, F. et al. Basic fibroblast growth factor expression is increased in human renalfibrogenesis and may mediate autocrine fibroblast proliferation. Kidney Int.57,1521–1538(2000).
80. Ostendorf, T., Eitner, F.&Floege, J. The PDGF family in renal fibrosis. Pediatr.Nephrol. http://dx.doi.org/10.1007/s00467-011-1892-z.
81. Hu, K. et al. tPA protects renal interstitial fibroblasts and myofibroblasts fromapoptosis. J. Am. Soc. Nephrol.19,503–514(2008).
82. Hao, S., Shen, H., Hou, Y., Mars, W. M.&Liu, Y. tPA is a potent mitogen for renalinterstitial fibroblasts: role of β1integrin/focal adhesion kinase. Am. J. Pathol.177,1164–1175(2010).
83. Lin, L. et al. tPA activates LDL receptor-related protein1-mediated mitogenicsignaling involving the p90RSK and GSK3β pathway. Am. J. Pathol.177,1687–1696(2010).
84. Hu, K., Wu, C., Mars, W. M.&Liu, Y. Tissue-type plasminogen activator promotesmurine myofibroblast activation through LDL receptor-related protein1-mediatedintegrin signaling. J. Clin. Invest.117,3821–3832(2007).
85. Hu, K. et al. Tissue-type plasminogen activator acts as a cytokine that triggersintracellularsignal transduction and induces matrix metalloproteinase-9geneexpression. J. Biol. Chem.281,2120–2127(2006).
86. Duffield, J. S.&Humphreys, B. D. Origin of new cells in the adult kidney: resultsfrom genetic labeling techniques. Kidney Int.79,494–501(2011).
87. Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin ofmyofibroblasts in kidney fibrosis. Am. J. Pathol.176,85–97(2010).
88. Kalluri, R.&Weinberg, R. A. The basics of epithelial-mesenchymal transition. J.Clin. Invest.119,1420–1428(2009).
89. Acloque, H., Adams, M. S., Fishwick, K., Bronner-Fraser, M.&Nieto, M. A.Epithelial-mesenchymal transitions: the importance of changing cell state indevelopment and disease. J. Clin. Invest.119,1438–1449(2009).
90. Sleeman, J. P.&Thiery, J. P. SnapShot: the epithelial-mesenchymal transition. Cell145,162.e1(2011).
91. Li, J., Qu, X.&Bertram, J. F. Endothelial-myofibroblast transition contributes to theearly development of diabetic renal interstitial fibrosis in streptozotocin-induceddiabetic mice. Am. J. Pathol.175,1380–1388(2009).
92. Zeisberg, E. M., Potenta, S. E., Sugimoto, H., Zeisberg, M.&Kalluri, R. Fibroblastsin kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc.Nephrol.19,2282–2287(2008).
93. Kriz, W., Kaissling, B.&Le Hir, M. Epithelial-mesenchymal transition (EMT) inkidney fibrosis: fact or fantasy? J. Clin. Invest.121,468–474(2011).
94. Zeisberg, M.&Duffield, J. S. Resolved: EMT produces fibroblasts in the kidney. J.Am. Soc. Nephrol.21,1247–1253(2010).
95. Liu, Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J. Am.Soc. Nephrol.21,212–222(2010).
96. Li, J.&Bertram, J. F. Endothelial-myofibroblast transition, a new player in diabeticrenal fibrosis. Nephrology15,507–512(2010).
97. Burns, W. C.&Thomas, M. C. The molecular mediators of type2epithelial tomesenchymal transition (EMT) and their role in renal pathophysiology. Expert Rev.Mol. Med.12, e17(2010).
98. Grgic, I., Duffield, J. S.&Humphreys, B. D. The origin of interstitialmyofibroblasts in chronic kidney disease. Pediatr. Nephrol. http://dx.doi.org/10.1007/s00467-011-1772-6.
99. Quaggin, S. E.&Kapus, A. Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transition. Kidney Int.80,41–50(2011).
100. Yang, J.&Liu, Y. Dissection of key events in tubular epithelial to myofibroblasttransition and its implications in renal interstitial fibrosis. Am. J. Pathol.159,1465–1475(2001).
101. Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissuefibrosis. J. Clin. Invest.110,341–350(2002).
102. Li, L., Zepeda-Orozco, D., Black, R.&Lin, F. Autophagy is a component ofepithelial cell fate in obstructive uropathy. Am. J. Pathol.176,1767–1778(2010).
103. Togawa, H. et al. Epithelial-to-mesenchymal transition in cyst lining epithelial cellsin an orthologous PCK rat model of autosomal-recessive polycystic kidney disease.Am. J. Physiol. Renal Physiol.300, F511–F520(2011).
104. Boonla, C. et al. Fibrosis and evidence for epithelial-mesenchymal transition in thekidneys of patients with staghorn calculi. BJU Int.108,1336–1345(2011).
105. Yang, J.&Liu, Y. Blockage of tubular epithelial to myofibroblast transition byhepatocyte growth factor prevents renal interstitial fibrosis. J. Am. Soc. Nephrol.13,96–107(2002).
106. Zeisberg, M. et al. BMP-7counteracts TGF-β1-induced epithelial-to-mesenchymaltransition and reverses chronic renal injury. Nat. Med.9,964–968(2003).
107. Hertig, A. et al. Early epithelial phenotypic changes predict graft fibrosis. J. Am. Soc.Nephrol.19,1584–1591(2008).
108. Galichon, P.&Hertig, A. Epithelial to mesenchymal transition as a biomarker inrenal fibrosis: are we ready for the bedside? Fibrogenesis Tissue Repair4,11(2011).
109. He, W. et al. Wnt/β-catenin signaling promotes renal interstitial fibrosis. J. Am. Soc.Nephrol.20,765–776(2009).
110. Li, Y. et al. Inhibition of integrin-linked kinase attenuates renal interstitial fibrosis. J.Am. Soc. Nephrol.20,1907–1918(2009).
111. Yang, J. et al. Disruption of tissue-type plasminogen activator gene in mice reducesrenal interstitial fibrosis in obstructive nephropathy. J. Clin. Invest.110,1525–1538(2002).
112. Liu, Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologicsignificance, molecular mechanism, and therapeutic intervention. J. Am. Soc.Nephrol.15,1–12(2004).
113. Surendran, K., Schiavi, S.&Hruska, K. A. Wnt-dependent β-catenin signaling isactivated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein4alters the progression of renal fibrosis. J. Am. Soc. Nephrol.16,2373–2384(2005).
114. Tan, X., Li, Y.&Liu, Y. Paricalcitol attenuates renal interstitial fibrosis inobstructive nephropathy. J. Am. Soc. Nephrol.17,3382–3393(2006).
115. Zhou, Y. et al. HSP72inhibits Smad3activation and nuclear translocation in renalepithelial-to-mesenchymal transition. J. Am. Soc. Nephrol.21,598–609(2010).
116. Herzog, E. L.&Bucala, R. Fibrocytes in health and disease. Exp. Hematol.38,548–556(2010).
117. Wada, T. et al. Involvement of bone-marrow-derived cells in kidney fibrosis. Clin.Exp. Nephrol.15,8–13(2011).
118. Pilling, D., Fan, T., Huang, D., Kaul, B.&Gomer, R. H. Identification of markersthat distinguish monocyte-derived fibrocytes from monocytes, macrophages, andfibroblasts. PLoS ONE4, e7475(2009).
119. Niedermeier, M. et al. CD4+T cells control the differentiation of Gr1+monocytesinto fibrocytes. Proc. Natl Acad. Sci. USA106,17892–17897(2009).
120. Shao, D. D., Suresh, R., Vakil, V., Gomer, R. H.&Pilling, D. Pivotal Advance: Th-1cytokines inhibit, and Th-2cytokines promote fibrocyte differentiation. J. Leukoc.Biol.83,1323–1333(2008).
121. Sakai, N. et al. The renin-angiotensin system contributes to renal fibrosis throughregulation of fibrocytes. J. Hypertens.26,780–790(2008).
122. Roufosse, C. et al. Bone marrow-derived cells do not contribute significantly tocollagen I synthesis in a murine model of renal fibrosis. J. Am. Soc. Nephrol.17,775–782(2006).
123. Yang, J., Dai, C.&Liu, Y. Hepatocyte growth factor suppresses renal interstitialmyofibroblast activation and intercepts Smad signal transduction. Am. J. Pathol.163,621–632(2003).
124. Schnaper, H. W. et al. TGF-β signal transduction in chronic kidney disease. Front.Biosci.14,2448–2465(2009).
125. Dai, C.&Liu, Y. Hepatocyte growth factor antagonizes the profibrotic action ofTGF-β1in mesangial cells by stabilizing Smad transcriptional corepressor TGIF. J.Am. Soc. Nephrol.15,1402–1412(2004).
126. Liu, Y. Hepatocyte growth factor in kidney fibrosis: therapeutic potential andmechanisms of action. Am. J. Physiol. Renal Physiol.287, F7–F16(2004).
127. Luo, D. D., Phillips, A.&Fraser, D. Bone morphogenetic protein-7inhibitsproximal tubular epithelial cell Smad3signaling via increased SnoN expression. Am.J. Pathol.176,1139–1147(2010).
128. Wang, B. et al. miR-200a prevents renal fibrogenesis through repression of TGF-β2expression. Diabetes60,280–287(2011).
129. Kato, M. et al. A microRNA circuit mediates transforming growth factor-β1autoregulation in renal glomerular mesangial cells. Kidney Int.80,358–368(2011).
130. Inui, M., Martello, G.&Piccolo, S. MicroRNA control of signal transduction. Nat.Rev. Mol. Cell Biol.11,252–263(2010).
131. Chung, A. C., Huang, X. R., Meng, X.&Lan, H. Y. miR-192mediatesTGF-β/Smad3-driven renal fibrosis. J. Am. Soc. Nephrol.21,1317–1325(2010).
132. Zhou, Q. et al. TGF-β-induced MiR-491-5p expression promotes Par-3degradationin rat proximal tubular epithelial cells. J. Biol. Chem.285,40019–40027(2010).
133. Eyden, B. Fibronexus junctions associated with in vivo human endothelium.Ultrastruct. Pathol.33,28–32(2009).
134. Margadant, C.&Sonnenberg, A. Integrin-TGF-β crosstalk in fibrosis, cancer andwound healing. EMBO Rep.11,97–105(2010).
135. Legate, K. R.&F ssler, R. Mechanisms that regulate adaptor binding to β-integrincytoplasmic tails. J. Cell Sci.122,187–198(2009).
136. Legate, K. R., Monta ez, E., Kudlacek, O.&F ssler, R. ILK, PINCH and parvin:the tIPP of integrin signalling. Nat. Rev. Mol. Cell Biol.7,20–31(2006).
137. Maydan, M. et al. Integrin-linked kinase is a functional Mn2+-dependent proteinkinase that regulates glycogen synthase kinase-3β (GSK-3β) phosphorylation. PLoSONE5, e12356(2010).
138. Fukuda, K., Gupta, S., Chen, K., Wu, C.&Qin, J. The pseudoactive site of ILK isessential for its binding to α-parvin and localization to focal adhesions. Mol. Cell36,819–830(2009).
139. He, W. et al. Plasminogen activator inhibitor-1is a transcriptional target of thecanonical pathway of Wnt/β-catenin signaling. J. Biol. Chem.285,24665–24675(2010).
140. ten Berge, D. et al. Wnt signaling mediates self-organization and axis formation inembryoid bodies. Cell Stem Cell3,508–518(2008).
141. Wu, C. PINCH, N(i)ck and the ILK: network wiring at cell-matrix adhesions. TrendsCell Biol.15,460–466(2005).
142. Li, Y., Dai, C., Wu, C.&Liu, Y. PINCH-1promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase. J. Am. Soc.Nephrol.18,2534–2543(2007).
143. Guo, L.&Wu, C. Regulation of fibronectin matrix deposition and cell proliferationby the PINCH–ILK–CH–ILKBP complex. FASEB J.16,1298–1300(2002).
144. Yeh, Y. C. et al. Transforming growth factor-β1induces Smad3-dependent β1integrin gene expression in epithelial-to-mesenchymaltransition during chronictubulointerstitial fibrosis. Am. J. Pathol.177,1743–1754(2010).
145. Li, Y., Yang, J., Dai, C., Wu, C.&Liu, Y. Role for integrin-linked kinase inmediating tubular epithelial to mesenchymal transition and renal interstitialfibrogenesis. J. Clin. Invest.112,503–516(2003).
146. Liu, X. C., Liu, B. C., Zhang, X. L., Li, M. X.&Zhang, J. D. Role of ERK1/2andPI3-K in the regulation of CTGF-induced ILK expression in HK-2cells. Clin. Chim.Acta382,89–94(2007).
147. Han, S. Y. et al. High glucose and angiotensin II increase β1integrin andintegrin-linked kinase synthesis in cultured mouse podocytes. Cell Tissue Res.323,321–332(2006).
148. Yang, F. et al. Essential role for Smad3in angiotensin II-induced tubularepithelial-mesenchymal transition. J. Pathol.221,390–401(2010).
149. Carvajal, G. et al. Angiotensin II activates the Smad pathway during epithelialmesenchymal transdifferentiation. Kidney Int.74,585–595(2008).
150. Yang, F., Chung, A. C., Huang, X. R.&Lan, H. Y. Angiotensin II inducesconnective tissue growth factor and collagen I expression via transforming growthfactor-β-dependent and-independent Smad pathways: the role of Smad3.Hypertension54,877–884(2009).
151. Eddy, A. A. Progression in chronic kidney disease. Adv. Chronic Kidney Dis.12,353–365(2005).
152. Bradshaw, A. D. The role of SPARC in extracellular matrix assembly. J. CellCommun. Signal.3,239–246(2009).
153. Weaver, M. S., Workman, G.&Sage, E. H. The copper binding domain of SPARCmediates cell survival in vitro via interaction with integrin β1and activation ofintegrin-linked kinase. J. Biol. Chem.283,22826–22837(2008).
154. Shweke, N. et al. Tissue transglutaminase contributes to interstitial renal fibrosis byfavoring accumulation of fibrillar collagen through TGF-β activation and cellinfiltration. Am. J. Pathol.173,631–642(2008).
155. Huang, L. et al. Transglutaminase inhibition ameliorates experimental diabeticnephropathy. Kidney Int.76,383–394(2009).
156. He, W., Kang, Y. S., Dai, C.&Liu, Y. Blockade of Wnt/β-catenin signaling byparicalcitol ameliorates proteinuria and kidney injury. J. Am. Soc. Nephrol.22,90–103(2011).
157. Sharma, S., Sirin, Y.&Susztak, K. The story of Notch and chronic kidney disease.Curr. Opin. Nephrol. Hypertens.20,56–61(2011).
158. Bielesz, B. et al. Epithelial Notch signaling regulates interstitial fibrosisdevelopment in the kidneys of mice and humans. J. Clin. Invest.120,4040–4054(2010).
159. Higgins, D. F. et al. Hypoxia promotes fibrogenesis in vivo via HIF-1stimulation ofepithelial-to-mesenchymal transition. J. Clin. Invest.117,3810–3820(2007).
160. Sun, S. et al. Hypoxia-inducible factor-1α induces Twist expression in tubularepithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition.Kidney Int.75,1278–1287(2009).
161. Kume, S. et al. Calorie restriction enhances cell adaptation to hypoxia throughSirt1-dependent mitochondrial autophagy in mouse aged kidney. J. Clin. Invest.120,1043–1055(2010).
162. Jiang, M., Liu, K., Luo, J.&Dong, Z. Autophagy is a renoprotective mechanismduring in vitro hypoxia and in vivo ischemia-reperfusion injury. Am. J. Pathol.176,1181–1192(2010).
163. Koesters, R. et al. Tubular overexpression of transforming growth factor-β1inducesautophagy and fibrosis but not mesenchymal transition of renal epithelialcells. Am. J. Pathol.177,632–643(2010).
164. Yang, L., Besschetnova, T. Y., Brooks, C. R., Shah, J. V.&Bonventre, J. V.Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat. Med.16,535–543(2010).
165. Wang, S. et al. Renal bone morphogenetic protein-7protects against diabeticnephropathy. J. Am. Soc. Nephrol.17,2504–2512(2006).
166. Tan, X., He, W.&Liu, Y. Combination therapy with paricalcitol and trandolaprilreduces renal fibrosis in obstructive nephropathy. Kidney Int.76,1248–1257(2009).
167. de Zeeuw, D. et al. Selective vitamin D receptor activation with paricalcitol forreduction of albuminuria in patients with type2diabetes (VITAL study): arandomised controlled trial. Lancet376,1543–1551(2010).
168. Mirkovic, K., van den Born, J., Navis, G.&de Borst, M. H. Vitamin D in chronickidney disease: new potential for intervention. Curr. Drug Targets12,42–53(2011).
169. Wang, X. et al. Mice lacking the matrix metalloproteinase-9gene reduce renalinterstitial fibrosis in obstructive nephropathy. Am. J. Physiol. Renal Physiol.299,F973–F982(2010).
170. Cheng, S., Pollock, A. S., Mahimkar, R., Olson, J. L.&Lovett, D. H. Matrixmetalloproteinase2and basement membrane integrity: a unifying mechanism forprogressive renal injury. FASEB J.20,1898–1900(2006).
171. Zeisberg, M. et al. Stage-specific action of matrix metalloproteinases influencesprogressive hereditary kidney disease. PLoS Med.3, e100(2006).
172. Li, J. et al. Blockade of endothelial-mesenchymal transition by a Smad3inhibitordelays the early development of streptozotocin-induced diabetic nephropathy.Diabetes59,2612–2624(2010).
173. Lin, S. L. et al. Targeting endothelium-pericyte cross talk by inhibiting VEGFreceptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am. J.Pathol.178,911–923(2011).
174. Venkatachalam, M. A. et al. Acute kidney injury: a springboard for progression inchronic kidney disease. Am. J. Physiol. Renal Physiol.298, F1078–F1094(2010).
175. Kelly, K. J., Burford, J. L.&Dominguez, J. H. Postischemic inflammatorysyndrome: a critical mechanism of progression in diabetic nephropathy. Am. J.Physiol. Renal Physiol.297, F923–F931(2009).
176. Guo, Z. J. et al. Advanced oxidation protein products activate vascular endothelialcells via a RAGE-mediated signaling pathway. Antioxid. Redox Signal.10,1699–1712(2008).
177. Wilkinson, L. et al. Loss of renal microvascular integrity in postnatal Crim1hypomorphic transgenic mice. Kidney Int.76,1161–1171(2009).
178. Mimura, I.&Nangaku, M. The suffocating kidney: tubulointerstitial hypoxia inend-stage renal disease. Nat. Rev. Nephrol.6,667–678(2010).
179. Touyz, R. M.&Briones, A. M. Reactive oxygen species and vascular biology:implications in human hypertension. Hypertens. Res.34,5–14(2011).
180. Fine, L. G.&Norman, J. T. Chronic hypoxia as a mechanism of progression ofchronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int.74,867–872(2008).
181. Gunaratnam, L.&Bonventre, J. V. HIF in kidney disease and development. J. Am.Soc. Nephrol.20,1877–1887(2009).
182. D’Agati, V.&Schmidt, A. M. RAGE and the pathogenesis of chronic kidney disease.Nat. Rev. Nephrol.6,352–360(2010).
183. Negre-Salvayre, A., Coatrieux, C., Ingueneau, C.&Salvayre, R. Advanced lipidperoxidation end products in oxidative damage to proteins. Potential role in diseasesand therapeutic prospects for the inhibitors. Br. J. Pharmacol.153,6–20(2008).
184. Zhou, L. L. et al. Accumulation of advanced oxidation protein products inducespodocyte apoptosis and deletion through NADPH-dependent mechanisms. KidneyInt.76,1148–1160(2009).
185. Shi, X. Y. et al. Advanced oxidation protein products promote inflammation indiabetic kidney through activation of renal nicotinamide adenine dinucleotidephosphate oxidase. Endocrinology149,1829–1839(2008).
186. Daroux, M. et al. Advanced glycation end-products: implications for diabetic andnon-diabetic nephropathies. Diabetes Metab.36,1–10(2010).
187. Shanmugam, N. et al. Proinflammatory effects of advanced lipoxidation endproducts in monocytes. Diabetes57,879–888(2008).
188. Bechtel, W. et al. Methylation determines fibroblast activation and fibrogenesis inthe kidney. Nat. Med.16,544–550(2010).
189. Hu, K., Mars, W. M.&Liu, Y. Novel actions of tissue-type plasminogen activator inchronic kidney disease. Front. Biosci.13,5174–5186(2008).
2. Pannarale G, Carbone R, Del Mastro G, Gallo C, Gattullo V, et al.(2010) The agingkidney: structural changes. J Nephrol23Suppl15: S37-40.
3. Strutz F (2001) Potential methods to prevent interstitial fibrosis in renal disease. ExpertOpin Investig Drugs10:1989-2001.
4. Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol7:684-696.
5. Tan X, Li Y, Liu Y (2007) Therapeutic role and potential mechanisms of active VitaminD in renal interstitial fibrosis. J Steroid Biochem Mol Biol103:491-496.
6. Hao S, He W, Li Y, Ding H, Hou Y, et al.(2011) Targeted inhibition ofbeta-catenin/CBP signaling ameliorates renal interstitial fibrosis. J Am Soc Nephrol22:1642-1653.
7. Klahr S, Morrissey J (2002) Obstructive nephropathy and renal fibrosis. Am J PhysiolRenal Physiol283: F861-875.
8. Vaughan ED, Jr., Marion D, Poppas DP, Felsen D (2004) Pathophysiology of unilateralureteral obstruction: studies from Charlottesville to New York. J Urol172:2563-2569.
9. Harris RC, Neilson EG (2006) Toward a unified theory of renal progression. Annu RevMed57:365-380.
10. Tapmeier TT, Fearn A, Brown K, Chowdhury P, Sacks SH, et al.(2010) Pivotal role ofCD4+T cells in renal fibrosis following ureteric obstruction. Kidney Int78:351-362.
11. Tian YC, Fraser D, Attisano L, Phillips AO (2003) TGF-beta1-mediated alterations ofrenal proximal tubular epithelial cell phenotype. Am J Physiol Renal Physiol285:F130-142.
12. Mucsi I, Rosivall L (2007) Epithelial-mesenchymal transition in renal tubular cells inthe pathogenesis of progressive tubulo-interstitial fibrosis. Acta Physiol Hung94:117-131.
13. Garcia GE, Truong LD, Li P, Zhang P, Du J, et al.(2008) Adenosine A2A receptoractivation and macrophage-mediated experimental glomerulonephritis. FASEB J22:445-454.
14. Mazzon E, Esposito E, Impellizzeri D, R DIP, Melani A, et al.(2011) CGS21680, anagonist of the adenosine (A2A) receptor, reduces progression of murine type IIcollagen-induced arthritis. J Rheumatol38:2119-2129.
15. Impellizzeri D, Di Paola R, Esposito E, Mazzon E, Paterniti I, et al.(2011) CGS21680,an agonist of the adenosine (A2A) receptor, decreases acute lung inflammation. Eur JPharmacol668:305-316.
16. Ferenbach DA, Hughes J (2011) Adenosine A(2A) agonists as therapy forglomerulonephritis. Kidney Int80:329-331.
17. Garcia GE, Truong LD, Chen JF, Johnson RJ, Feng L (2011) Adenosine A(2A) receptoractivation prevents progressive kidney fibrosis in a model of immune-associatedchronic inflammation. Kidney Int80:378-388.
18. Zhang L, Yang N, Wang S, Huang B, Li F, et al.(2011) Adenosine2A receptor isprotective against renal injury in MRL/lpr mice. Lupus20:667-677.
19. Sohail MA, Hashmi AZ, Hakim W, Watanabe A, Zipprich A, et al.(2009) Adenosineinduces loss of actin stress fibers and inhibits contraction in hepatic stellate cells viaRho inhibition. Hepatology49:185-194.
1. Hostetter TH, Olson JL, Rennke HG et al. Hyperfiltration in remnant nephrons: apotentially adverse response to renal ablation. Am J Physiol1981;241: F85–F93.
2. Ma LJ, Fogo AB. Model of robust induction of glomerulosclerosis in mice: Importanceof genetic background. Kidney Int2003;64:350–355.
3. Schnaper HW, Kopp JB. Why kidneys fail: Report from an American Society ofNephrology Advances in Research Conference. J Am Soc Nephol2006;17:1777–1781.
4. Schainuck LI, Striker GE, Cutler RE et al. Structural-functional correlations in renaldisease. Part II: The correlations. Hum Pathol1970;1:631–641.
5. Nagle RB, Bulger RE, Cutler RE et al. Unilateral obstructive nephropathy in therabbit:I. Early morphologic, physiologic, and histochemical changes. Lab Invest1973;28:456–467.
6. Sharma AK, Mauer SM, Kim Y et al. Interstitial fibrosis in obstructive nephropathy.Kidney Int1993;44:774–788.
7. Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis. Am J Physiol2002;283:F861–F875.
8. Eddy AA. Can renal fibrosis be reversed? Pediatr Nephrol2005;20:1369–1375.
9. Chevalier RL. Counterbalance in functional adaptation to ureteral obstruction duringdevelopment. Pediatr Nephrol1990;4:442–444.
10. Hironaka K, Sakaida I, Uchida K et al. Correlation between stellate cell activation andserum fibrosis markers in choline-deficient L-amino acid-defined diet-induced rat liverfibrosis. Dig Dis Sci2000;45:1935–1943.
11. Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol2000;15:290–301.
12. Kriz W, LeHir M. Pathways to nephron loss starting from glomerular diseases–Insightsfrom animal models. Kidney Int2005;67:404–419.
13. Tashiro K, Tamada S, Kuwabara N et al. Attenuation of renal fibrosis by proteasomeinhibition in rat obstructive nephropathy: possible role of nuclear factor kappaB. Int JMol Med2003;12:587–592.
14. Miyajima A, Kosaka T, Seta K et al. Novel nuclear factor kappaB activation inhibitorprevents inflammatory injury in unilateral ureteral obstruction. J Urol2003;169:1559–1563.
15. Iwano M, Plieth D, Danoff TM et al. Evidence that fibroblasts derive from epitheliumduring tissue fibrosis. J Clin Invest2002;110:341–350.
16. Zeisberg EM, Potenta SE, Sugimoto H et al. Fibroblasts in kidney fibrosis emerge viaendothelial-to-mesenchymal transition. J Am Soc Nephrol2008;19:2282–2287.
17. Ohashi R, Shimizu A, Masuda Y et al. Peritubular capillary regression during theprogression of experimental obstructive nephropathy. J Am Soc Nephrol2002;13:1795–1805.
18. Lin SL, Kisseleva T, Brenner DA et al. Pericytes and perivascular fibroblasts are theprimary source of collagen-producing cells in obstructive fibrosis of the kidney. Am JPathol2008;173:1617–1627.
19. Bascands JL, Schanstra JP. Obstructive nephropathy: insights from geneticallyengineered animals. Kidney Int2005;68:925–937.
20. Chevalier RL. Obstructive nephropathy: towards biomarker discovery and gene therapy.Nat Clin Prac Nephrol2006;2:157–168.
21. Chevalier RL, Cachat F. Role of angiotensin II in chronic ureteral obstruction. In: WolfG (ed). The Renin-Angiotensin System and Progression of Renal Diseases.1ed.Karger: Basel,2001pp250–260.
22. Pittock ST, Norby SM, Grande JP et al. MCP-1is up-regulated in unstressed andstressed HO-1knockout mice: Pathophysiologic correlates. Kidney Int2005;68:611–622.
23. Miyajima A, Chen J, Lawrence C et al. Antibody to transforming growth factor-bameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int2000;58:2301–2313.
24. Morrissey J, Hurska K, Guo G et al. Bone morphogenetic protein-7improves renalfibrosis and accelerates the return of renal function. J Am Soc Nephrol2002;13:S14–S21.
25. Zhang G, Kim H, Cai X et al. Urokinase receptor deficiency accelerates renal fibrosis inobstructive nephropathy. J Am Soc Nephrol2005;14:1254–1271.
26. Docherty NG, O’Sullivan OE, Healy DA et al. Evidence that inhibition of tubular cellapoptosis protects against renal damage and development of fibrosis following uretericobstruction. Am J Physiol Renal Physiol2006;290: F4–F13, Jan.F4-13,/1.
27. Morrissey JJ, Klahr S. Effect of AT2receptor blockade on the pathogenesis of renalfibrosis. Am J Physiol Renal Physiol1999;276: F39–F45.
28. Duffield JS. The inflammatory macrophage: a story of Jekyll and Hyde. Clin Sci2003;104:27–38.
29. Eardley KS, Cockwell P. Macrophages and progressive tubulointerstitial disease.Kidney Int2005;68:437–455.
30. Chevalier RL. Pathogenesis of renal injury in obstructive uropathy. Curr Opin Pediatr2006;18:153–160.
31. Yoo KH, Thornhill BA, Forbes MS et al. Osteopontin regulates renal apoptosis andinterstitial fibrosis in neonatal chronic unilateral ureteral obstruction. Kidney Int2006;70:1735–1741.
32. Rouschop KMA, Sewnath ME, Claessen N et al. CD44deficiency increases tubulardamage but reduces renal fibrosis in obstructive nephropathy. J Am Soc Nephrol2004;15:674–686.
33. Yukawa K, Hoshino K, Kishino M et al. Deletion of the kinase domain indeath-associated protein kinase attenuates renal tubular cell apoptosis in chronicobstructive uropathy. Int J Mol Med2004;13:515–520.
1. Isaka Y, Takahara S, Imai E. Chronic deteriorating renal function and renal fibrosis.Contrib Nephrol2008,159:109-121.
2. Pannarale G, Carbone R, Del Mastro G, Gallo C, Gattullo V, Natalicchio L, et al. Theaging kidney: structural changes. J Nephrol2010,23Suppl15:S37-40.
3. Chevalier RL. Molecular and cellular pathophysiology of obstructive nephropathy.Pediatr Nephrol1999,13:612-619.
4. Vielhauer V, Allam R, Lindenmeyer MT, Cohen CD, Draganovici D, Mandelbaum J, etal. Efficient renal recruitment of macrophages and T cells in mice lacking the duffyantigen/receptor for chemokines. Am J Pathol2009,175:119-131.
5. Lian YG, Zhou QG, Zhang YJ, Zheng FL. VEGF ameliorates tubulointerstitial fibrosisin unilateral ureteral obstruction mice via inhibition of epithelial-mesenchymaltransition. Acta Pharmacol Sin2011,32:1513-1521.
6. Nasu T, Kinomura M, Tanabe K, Yamasaki H, Htay SL, Saito D, et al. Asustained-release prostacyclin analog ONO-1301ameliorates tubulointerstitialalterations in a mouse obstructive nephropathy model. Am J Physiol Renal Physiol2012.
7. Omori H, Kawada N, Inoue K, Ueda Y, Yamamoto R, Matsui I, et al. Use of xanthineoxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis inunilateral ureteral obstructive nephropathy. Clin Exp Nephrol2012.
8. Guerrot D, Kerroch M, Placier S, Vandermeersch S, Trivin C, Mael-Ainin M, et al.Discoidin domain receptor1is a major mediator of inflammation and fibrosis inobstructive nephropathy. Am J Pathol2011,179:83-91.
9. Fernandez P, Trzaska S, Wilder T, Chiriboga L, Blackburn MR, Cronstein BN, et al.Pharmacological blockade of A2A receptors prevents dermal fibrosis in a model ofelevated tissue adenosine. Am J Pathol2008,172:1675-1682.
10. Chan ES, Montesinos MC, Fernandez P, Desai A, Delano DL, Yee H, et al. AdenosineA(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol2006,148:1144-1155.
11. Garcia GE, Truong LD, Chen JF, Johnson RJ, Feng L. Adenosine A(2A) receptoractivation prevents progressive kidney fibrosis in a model of immune-associatedchronic inflammation. Kidney Int2011,80:378-388.
12. Chen JF, Huang Z, Ma J, Zhu J, Moratalla R, Standaert D, et al. A(2A) adenosinereceptor deficiency attenuates brain injury induced by transient focal ischemia in mice.J Neurosci1999,19:9192-9200.
13. Moriyama T, Kawada N, Ando A, Yamauchi A, Horio M, Nagata K, et al.Up-regulation of HSP47in the mouse kidneys with unilateral ureteral obstruction.Kidney Int1998,54:110-119.
14. Luo L, Sun Z, Wu W, Luo G. Mycophenolate mofetil and FK506have different effectson kidney allograft fibrosis in rats that underwent chronic allograft nephropathy. BMCNephrol2012,13:53.
15. Iwano M. EMT and TGF-beta in renal fibrosis. Front Biosci (Schol Ed)2010,2:229-238.
16. Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol2010,21:1819-1834.
17. Rebola N, Simoes AP, Canas PM, Tome AR, Andrade GM, Barry CE, et al. AdenosineA2A receptors control neuroinflammation and consequent hippocampal neuronaldysfunction. J Neurochem2011,117:100-111.
18. Scheibner KA, Boodoo S, Collins S, Black KE, Chan-Li Y, Zarek P, et al. Theadenosine a2a receptor inhibits matrix-induced inflammation in a novel fashion. Am JRespir Cell Mol Biol2009,40:251-259.
19. Warren CA, Calabrese GM, Li Y, Pawlowski SW, Figler RA, Rieger J, et al. Effects ofadenosine A(2)A receptor activation and alanyl-glutamine in Clostridium difficiletoxin-induced ileitis in rabbits and cecitis in mice. BMC Infect Dis2012,12:13.
20. Lukashev D, Ohta A, Apasov S, Chen JF, Sitkovsky M. Cutting edge: Physiologicattenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosinereceptor in vivo. J Immunol2004,173:21-24.
21. Sitkovsky M, Lukashev D, Deaglio S, Dwyer K, Robson SC, Ohta A. Adenosine A2Areceptor antagonists: blockade of adenosinergic effects and T regulatory cells. Br JPharmacol2008,153Suppl1:S457-464.
22. Heinrich EL, Walser TC, Krysan K, Liclican EL, Grant JL, Rodriguez NL, et al. Theinflammatory tumor microenvironment, epithelial mesenchymal transition and lungcarcinogenesis. Cancer Microenviron2012,5:5-18.
23. Meng LQ, Tang JW, Wang Y, Zhao JR, Shang MY, Zhang M, et al. Astragaloside IVsynergizes with ferulic acid to inhibit renal tubulointerstitial fibrosis in rats withobstructive nephropathy. Br J Pharmacol2011,162:1805-1818.
24. Burns WC, Kantharidis P, Thomas MC. The role of tubular epithelial-mesenchymaltransition in progressive kidney disease. Cells Tissues Organs2007,185:222-231.
25. Mucsi I, Rosivall L. Epithelial-mesenchymal transition in renal tubular cells in thepathogenesis of progressive tubulo-interstitial fibrosis. Acta Physiol Hung2007,94:117-131.
26. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, et al.Transforming growth factor-beta1mediates epithelial to mesenchymal transdifferentiationthrough a RhoA-dependent mechanism. Mol Biol Cell2001,12:27-36.
27. Sohail MA, Hashmi AZ, Hakim W, Watanabe A, Zipprich A, Groszmann RJ, et al.Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellatecells via Rho inhibition. Hepatology2009,49:185-194.
1. Isaka Y, Takahara S, Imai E (2008) Chronic deteriorating renal function and renalfibrosis. Contrib Nephrol159:109-121.
2. Pannarale G, Carbone R, Del Mastro G, Gallo C, Gattullo V, et al.(2010) The agingkidney: structural changes. J Nephrol23Suppl15: S37-40.
3. Strutz F (2001) Potential methods to prevent interstitial fibrosis in renal disease. ExpertOpin Investig Drugs10:1989-2001.
4. Mucsi I, Rosivall L (2007) Epithelial-mesenchymal transition in renal tubular cells inthe pathogenesis of progressive tubulo-interstitial fibrosis. Acta Physiol Hung94:117-131.
5. Tan X, Li Y, Liu Y (2007) Therapeutic role and potential mechanisms of active VitaminD in renal interstitial fibrosis. J Steroid Biochem Mol Biol103:491-496.
6. Hao S, He W, Li Y, Ding H, Hou Y, et al.(2011) Targeted inhibition of beta-catenin/CBPsignaling ameliorates renal interstitial fibrosis. J Am Soc Nephrol22:1642-1653.
7. Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol7:684-696.
8. Iwano M (2010) EMT and TGF-beta in renal fibrosis. Front Biosci (Schol Ed)2:229-238.
9. Zeisberg M, Neilson EG (2010) Mechanisms of tubulointerstitial fibrosis. J Am SocNephrol21:1819-1834.
10. Klahr S, Morrissey J (2002) Obstructive nephropathy and renal fibrosis. Am J PhysiolRenal Physiol283: F861-875.
11. Vaughan ED, Jr., Marion D, Poppas DP, Felsen D (2004) Pathophysiology of unilateralureteral obstruction: studies from Charlottesville to New York. J Urol172:2563-2569.
12. Harris RC, Neilson EG (2006) Toward a unified theory of renal progression. Annu RevMed57:365-380.
13. Tapmeier TT, Fearn A, Brown K, Chowdhury P, Sacks SH, et al.(2010) Pivotal role ofCD4+T cells in renal fibrosis following ureteric obstruction. Kidney Int78:351-362.
14. Tian YC, Fraser D, Attisano L, Phillips AO (2003) TGF-beta1-mediated alterations ofrenal proximal tubular epithelial cell phenotype. Am J Physiol Renal Physiol285:F130-142.
15. Mazzon E, Esposito E, Impellizzeri D, R DIP, Melani A, et al.(2011) CGS21680, anagonist of the adenosine (A2A) receptor, reduces progression of murine type IIcollagen-induced arthritis. J Rheumatol38:2119-2129.
16. Impellizzeri D, Di Paola R, Esposito E, Mazzon E, Paterniti I, et al.(2011) CGS21680,an agonist of the adenosine (A2A) receptor, decreases acute lung inflammation. Eur JPharmacol668:305-316.
17. Ferenbach DA, Hughes J (2011) Adenosine A(2A) agonists as therapy for glomerulonephritis.Kidney Int80:329-331.
18. Garcia GE, Truong LD, Chen JF, Johnson RJ, Feng L (2011) Adenosine A(2A) receptoractivation prevents progressive kidney fibrosis in a model of immune-associatedchronic inflammation. Kidney Int80:378-388.
19. Zhang L, Yang N, Wang S, Huang B, Li F, et al.(2011) Adenosine2A receptor isprotective against renal injury in MRL/lpr mice. Lupus20:667-677.
20. Sohail MA, Hashmi AZ, Hakim W, Watanabe A, Zipprich A, et al.(2009) Adenosineinduces loss of actin stress fibers and inhibits contraction in hepatic stellate cells viaRho inhibition. Hepatology49:185-194.
21. Chen JF, Huang Z, Ma J, Zhu J, Moratalla R, et al.(1999) A(2A) adenosine receptordeficiency attenuates brain injury induced by transient focal ischemia in mice. JNeurosci19:9192-9200.
22. Mao H, Li Z, Zhou Y, Zhuang S, An X, et al.(2008) HSP72attenuates renal tubular cellapoptosis and interstitial fibrosis in obstructive nephropathy. Am J Physiol RenalPhysiol295: F202-214.
23. Wu G, Tu Y, Jia R (2010) The influence of fasudil on the epithelial-mesenchymaltransdifferentiation of renal tubular epithelial cells from diabetic rats. BiomedPharmacother64:124-129.
24. Zheng G, Wang Y, Mahajan D, Qin X, Alexander SI, et al.(2005) The role oftubulointerstitial inflammation. Kidney Int Suppl: S96-100.
25. Tipping PG, Holdsworth SR (2006) T cells in crescentic glomerulonephritis. J Am SocNephrol17:1253-1263.
26. Strutz F, Neilson EG (1994) The role of lymphocytes in the progression of interstitialdisease. Kidney Int Suppl45: S106-110.
27. Yang N, Isbel NM, Nikolic-Paterson DJ, Li Y, Ye R, et al.(1998) Local macrophageproliferation in human glomerulonephritis. Kidney Int54:143-151.
28. Robertson H, Ali S, McDonnell BJ, Burt AD, Kirby JA (2004) Chronic renal allograftdysfunction: the role of T cell-mediated tubular epithelial to mesenchymal celltransition. J Am Soc Nephrol15:390-397.
29. Vielhauer V, Anders HJ, Mack M, Cihak J, Strutz F, et al.(2001) Obstructivenephropathy in the mouse: progressive fibrosis correlates with tubulointerstitialchemokine expression and accumulation of CC chemokine receptor2-and5-positiveleukocytes. J Am Soc Nephrol12:1173-1187.
30. Eis V, Luckow B, Vielhauer V, Siveke JT, Linde Y, et al.(2004) Chemokine receptorCCR1but not CCR5mediates leukocyte recruitment and subsequent renal fibrosis afterunilateral ureteral obstruction. J Am Soc Nephrol15:337-347.
31. Kitagawa K, Wada T, Furuichi K, Hashimoto H, Ishiwata Y, et al.(2004) Blockade ofCCR2ameliorates progressive fibrosis in kidney. Am J Pathol165:237-246.
32. Anders HJ, Vielhauer V, Frink M, Linde Y, Cohen CD, et al.(2002) A chemokinereceptor CCR-1antagonist reduces renal fibrosis after unilateral ureter ligation. J ClinInvest109:251-259.
33. Lukashev D, Ohta A, Apasov S, Chen JF, Sitkovsky M (2004) Cutting edge: Physiologicattenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosinereceptor in vivo. J Immunol173:21-24.
34. Sitkovsky M, Lukashev D, Deaglio S, Dwyer K, Robson SC, et al.(2008) AdenosineA2A receptor antagonists: blockade of adenosinergic effects and T regulatory cells. Br JPharmacol153Suppl1: S457-464.
35. Pozdzik AA, Salmon IJ, Husson CP, Decaestecker C, Rogier E, et al.(2008) Patterns ofinterstitial inflammation during the evolution of renal injury in experimentalaristolochic acid nephropathy. Nephrol Dial Transplant23:2480-2491.
36. Tang TT, Yuan J, Zhu ZF, Zhang WC, Xiao H, et al.(2012) Regulatory T cellsameliorate cardiac remodeling after myocardial infarction. Basic Res Cardiol107:232.
37. Ohta A, Kini R, Subramanian M, Madasu M, Sitkovsky M (2012) The development andimmunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells areunder influence of the adenosine-A2A adenosine receptor pathway. Front Immunol3:190.
38. Zhou B, Buckley ST, Patel V, Liu Y, Luo J, et al.(2012) Troglitazone attenuatesTGF-beta1-induced EMT in alveolar epithelial cells via a PPARgamma-independentmechanism. PLoS One7: e38827.
39. Masszi A, Di Ciano C, Sirokmany G, Arthur WT, Rotstein OD, et al.(2003) Central rolefor Rho in TGF-beta1-induced alpha-smooth muscle actin expression duringepithelial-mesenchymal transition. Am J Physiol Renal Physiol284: F911-924.
40. Prakash J, de Borst MH, Lacombe M, Opdam F, Klok PA, et al.(2008) Inhibition ofrenal rho kinase attenuates ischemia/reperfusion-induced injury. J Am Soc Nephrol19:2086-2097.
41. Kalaji R, Wheeler AP, Erasmus JC, Lee SY, Endres RG, et al.(2012) ROCK1andROCK2regulate epithelial polarisation and geometric cell shape. Biol Cell.
42. Baum B, Georgiou M (2011) Dynamics of adherens junctions in epithelial establishment,maintenance, and remodeling. J Cell Biol192:907-917.
43. Otsu K, Kishigami R, Fujiwara N, Ishizeki K, Harada H (2011) Functional role ofRho-kinase in ameloblast differentiation. J Cell Physiol226:2527-2534.
44. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, et al.(2001) Transforminggrowth factor-beta1mediates epithelial to mesenchymal transdifferentiation through aRhoA-dependent mechanism. Mol Biol Cell12:27-36.
45. Fu P, Liu F, Su S, Wang W, Huang XR, et al.(2006) Signaling mechanism of renalfibrosis in unilateral ureteral obstructive kidney disease in ROCK1knockout mice. JAm Soc Nephrol17:3105-3114.
1. Hewitson TD. Renal tubulointerstitial fibrosis: common but never simple. Am J PhysiolRenal Physiol2009;296: F1239–F1244.
2. Tipping PG, Kitching AR. Glomerulonephritis, Th1and Th2: what’s new? Clin ExpImmunol2005;142:207–215.
3. Strutz F, Neilson EG. The role of lymphocytes in the progression of interstitial disease.Kidney Int Suppl1994;45: S106–S110.
4. Yang N, Isbel NM, Nikolic-Paterson DJ et al.Local macrophage proliferation in humanglomerulonephritis. Kidney Int1998;54:143–151.
5. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol2008;214:199–210.
6. Shappell SB, Gurpinar T, Lechago J et al. Chronic obstructive uropathy in severecombined immunodeficient (SCID) mice: lymphocyte infiltration is not required forprogressive tubulointerstitial injury. J Am Soc Nephrol1998;9:1008–1017.
7. Niedermeier M, Reich B, Rodriguez Gomez M et al. CD4+T cells control thedifferentiation of Gr1+monocytes into fibrocytes. Proc Natl Acad Sci USA2009;106:17892–17897.
8. Lin SL, Kisseleva T, Brenner DA e t al. Pericytes and perivascular fibroblasts are theprimary source ofcollagen-producing cells in obstructive fibrosis of the kidney. A m JPathol2008;173:1617–1627.
9. Roufosse C, Bou-Gharios G, Prodromidi E e t al. Bone marrow-derived cells do notcontribute significantly to collagen I synthesis in a murine model of renal fibrosis. J AmSoc Nephrol2006;17:775–782.
10. Tapmeier TT, Fearn A, Brown K et al. Pivotal role of CD4+T cells in renal fibrosisfollowing ureteric obstruction. K idney Int2010;78:351–362.
11. Henderson NC, Mackinnon AC, Farnworth SL et al. Galectin-3expression andsecretion links macrophages to the promotion of renal fibrosis. Am J Pathol2008;172:288–298.
12. Ma F, Liu J, Kitching AR e t al. Targeting renal macrophage accumulation throughinhibition of c-fms kinase activity reduces tubular apoptosis but fails to modifyprogressive fibrosis in the obstructed kidney. A m J Physiol Renal Physiol2009;296:F177–F185.
13. Isaka Y, Tsujie M, Ando Y e t al. Transforming growth factor-beta1antisenseoligodeoxynucleotidesblock interstitial fibrosis in unilateral ureteral obstruction.Kidney Int2000;58:1885–1892.
14. Humphreys BD, Lin SL, Kobayashi A e t al. Fate tracing reveals the pericyte and notepithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol2010;176:85–97.
1. Coresh, J. et al. Prevalence of chronic kidney disease in the United States. JAMA298,2038–2047(2007).
2. United States Renal Data System. Annual Data Report2009[online], http://www.usrds.org/adr.htm (2010).
3. Sharma, S. K. et al. Burden of CKD, proteinuria, and cardiovascular risk amongChinese, Mongolian, and Nepalese participants in the International Society ofNephrology screening programs. Am. J. Kidney Dis.56,915–927(2010).
4. Zhang, L. et al. Prevalence and factors associated with CKD: a population studyfrom Beijing. Am. J. Kidney Dis.51,373–384(2008).
5. Liu, Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. KidneyInt.69,213–217(2006).
6. Wynn, T. A. Cellular and molecular mechanisms of fibrosis. J. Pathol.214,199–210(2008).
7. Zeisberg, M.&Neilson, E. G. Mechanisms of tubulointerstitial fibrosis. J. Am. Soc.Nephrol.21,1819–1834(2010).
8. Boor, P., Ostendorf, T.&Floege, J. Renal fibrosis: novel insights into mechanismsand therapeutic targets. Nat. Rev. Nephrol.6,643–656(2010).
9. Li, Y. et al. Epithelial-to-mesenchymal transition is a potential pathway leading topodocyte dysfunction and proteinuria. Am. J. Pathol.172,299–308(2008).
10. Yamaguchi, Y. et al. Epithelial-mesenchymal transition as an explanation forpodocyte depletion in diabetic nephropathy. Am. J. Kidney Dis.54,653–664(2009).
11. Kang, Y. S. et al. Inhibition of integrin-linked kinase blocks podocyte epithelial-mesenchymal transition and ameliorates proteinuria. Kidney Int.78,363–373(2010).
12. Eddy, A. A. Molecular basis of renal fibrosis. Pediatr. Nephrol.15,290–301(2000).
13. Chung, A. C.&Lan, H. Y. Chemokines in renal injury. J. Am. Soc. Nephrol.22,802–809(2011).
14. Schroder, K.&Tschopp, J. The inflammasomes. Cell140,821–832(2010).
15. Nathan, C.&Ding, A. Nonresolving inflammation. Cell140,871–882(2010).
16. Vielhauer, V., Kulkarni, O., Reichel, C. A.&Anders, H. J. Targeting the recruitmentof monocytes and macrophages in renal disease. Semin. Nephrol.30,318–333(2010).
17. Vernon, M. A., Mylonas, K. J.&Hughes, J. Macrophages and renal fibrosis. Semin.Nephrol.30,302–317(2010).
18. Duffield, J. S. Macrophages and immunologic inflammation of the kidney. Semin.Nephrol.30,234–254(2010).
19. Ricardo, S. D., van Goor, H.&Eddy, A. A. Macrophage diversity in renal injury andrepair. J. Clin. Invest.118,3522–3530(2008).
20. Wang, Y.&Harris, D. C. Macrophages in renal disease. J. Am. Soc. Nephrol.22,21–27(2011).
21. Grande, M. T., Pérez-Barriocanal, F.&López-Novoa, J. M. Role of inflammation intubulo-interstitial damage associated to obstructive nephropathy. J. Inflamm.7,19(2010).
22. Tapmeier, T. T. et al. Pivotal role of CD4+T cells in renal fibrosis following uretericobstruction. Kidney Int.78,351–362(2010).
23. Lin, S. L., Casta o, A. P., Nowlin, B. T., Lupher, M. L. Jr&Duffield, J. S. Bonemarrow Ly6Chigh monocytes are selectively recruited to injured kidney anddifferentiate into functionally distinct populations. J. Immunol.183,6733–6743(2009).
24. Henderson, N. C. et al. Galectin-3expression and secretion links macrophages to thepromotion of renal fibrosis. Am. J. Pathol.172,288–298(2008).
25. Ko, G. J., Boo, C. S., Jo, S. K., Cho, W. Y.&Kim, H. K. Macrophages contribute tothe development of renal fibrosis following ischaemia/reperfusion-induced acutekidney injury. Nephrol. Dial. Transplant.23,842–852(2008).
26. Wang, Y. et al. By homing to the kidney, activated macrophages potently exacerbaterenal injury. Am. J. Pathol.172,1491–1499(2008).
27. Kaissling, B.&Le Hir, M. The renal cortical interstitium: morphological andfunctional aspects. Histochem. Cell Biol.130,247–262(2008).
28. John, R.&Nelson, P. J. Dendritic cells in the kidney. J. Am. Soc. Nephrol.18,2628–2635(2007).
29. Teteris, S. A., Engel, D. R.&Kurts, C. Homeostatic and pathogenic role of renaldendritic cells. Kidney Int.80,139–145(2011).
30. Macconi, D. et al. Proteasomal processing of albumin by renal dendritic cellsgenerates antigenic peptides. J. Am. Soc. Nephrol.20,123–130(2009).
31. Heymann, F. et al. Kidney dendritic cell activation is required for progression ofrenal disease in a mouse model of glomerular injury. J. Clin. Invest.119,1286–1297(2009).
32. Hochheiser, K. et al. Kidney dendritic cells become pathogenic during crescenticglomerulonephritis with proteinuria. J. Am. Soc. Nephrol.22,306–316(2011).
33. Timoshanko, J. R., Kitching, A. R., Semple, T. J., Tipping, P. G.&Holdsworth, S. R.A pathogenetic role for mast cells in experimental crescentic glomerulonephritis. J.Am. Soc. Nephrol.17,150–159(2006).
34. Holdsworth, S. R.&Summers, S. A. Role of mast cells in progressive renal diseases.J. Am. Soc. Nephrol.19,2254–2261(2008).
35. Kanamaru, Y. et al. Mast cell-mediated remodeling and fibrinolytic activity protectagainst fatal glomerulonephritis. J. Immunol.176,5607–5615(2006).
36. Anders, H. J. et al. A chemokine receptor CCR-1antagonist reduces renal fibrosisafter unilateral ureter ligation. J. Clin. Invest.109,251–259(2002).
37. Sayyed, S. G. et al. An orally active chemokine receptor CCR2antagonist preventsglomerulosclerosis and renal failure in type2diabetes. Kidney Int.80,68–78(2011).
38. Tan, X., Wen, X.&Liu, Y. Paricalcitol inhibits renal inflammation by promotingvitamin D receptor-mediated sequestration of NF-κB signaling. J. Am. Soc. Nephrol.19,1741–1752(2008).
39. Wen, X., Li, Y.&Liu, Y. Opposite action of peroxisome proliferator-activatedreceptor-γ in regulating renal inflammation: functional switch by its ligand. J. Biol.Chem.285,29981–29988(2010).
40. Kawai, T. et al. PPAR-γ agonist attenuates renal interstitial fibrosis andinflammation through reduction of TGF-β. Lab. Invest.89,47–58(2009).
41. Khan, S. B. et al. Antibody blockade of TNF-α reduces inflammation and scarring inexperimental crescentic glomerulonephritis. Kidney Int.67,1812–1820(2005).
42. Giannopoulou, M. et al. Hepatocyte growth factor exerts its anti-inflammatoryaction by disrupting nuclear factor-κB signaling. Am. J. Pathol.173,30–41(2008).
43. Gong, R., Rifai, A.&Dworkin, L. D. Anti-inflammatory effect of hepatocyte growthfactor in chronic kidney disease: targeting the inflamed vascular endothelium. J. Am.Soc. Nephrol.17,2464–2473(2006).
44. Jones, L. K. et al. IL-1RI deficiency ameliorates early experimental renal interstitialfibrosis. Nephrol. Dial. Transplant.24,3024–3032(2009).
45. Yu, C., Gong, R., Rifai, A., Tolbert, E. M.&Dworkin, L. D. Long-term, high-dosagecandesartan suppresses inflammation and injury in chronic kidney disease:nonhemodynamic renal protection. J. Am. Soc. Nephrol.18,750–759(2007).
46. Pate, M., Damarla, V., Chi, D. S., Negi, S.&Krishnaswamy, G. Endothelial cellbiology: role in the inflammatory response. Adv. Clin. Chem.52,109–130(2010).
47. López-Novoa, J. M.&Nieto, M. A. Inflammation and EMT: an alliance towardsorgan fibrosis and cancer progression. EMBO Mol. Med.1,303–314(2009).
48. Nightingale, J. et al. Oncostatin M, a cytokine released by activated mononuclearcells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathwayactivation. J. Am. Soc. Nephrol.15,21–32(2004).
49. Li, Q. et al. Monocytes induce proximal tubular epithelial mesenchymal transitionthrough NF-κB dependent upregulation of ICAM-1. J. Cell. Biochem.112,1585–1592(2011).
50. Wu, Y. et al. Stabilization of snail by NF-κB is required for inflammation-inducedcell migration and invasion. Cancer Cell15,416–428(2009).
51. Boutet, A. et al. Snail activation disrupts tissue homeostasis and induces fibrosis inthe adult kidney. EMBO J.25,5603–5613(2006).
52. Rowe, R. G. et al. Mesenchymal cells reactivate Snail1expression to drivethree-dimensional invasion programs. J. Cell Biol.184,399–408(2009).
53. Thiery, J. P., Acloque, H., Huang, R. Y.&Nieto, M. A. Epithelial-mesenchymaltransitions in development and disease. Cell139,871–890(2009).
54. Inoue, T. et al. Fibroblast expression of an IκB dominant-negative transgeneattenuates renal fibrosis. J. Am. Soc. Nephrol.21,2047–2052(2010).
55. Li, Y., Yang, J., Luo, J. H., Dedhar, S.&Liu, Y. Tubular epithelial celldedifferentiation is driven by the helix-loop-helix transcriptional inhibitor Id1. J. Am.Soc. Nephrol.18,449–460(2007).
56. Yang, Y., Liou, H. C.&Sun, X. H. Id1potentiates NF-κB activation upon T cellreceptor signaling. J. Biol. Chem.281,34989–34996(2006).
57. Lin, J. et al. Inhibitor of differentiation1contributes to head and neck squamous cellcarcinoma survival via the NF-κB/survivin and phosphoinositide3-kinase/Aktsignaling pathways. Clin. Cancer Res.16,77–87(2010).
58. Duffield, J. S. Macrophages in kidney repair and regeneration. J. Am. Soc. Nephrol.22,199–201(2011).
59. Gandolfo, M. T. et al. Foxp3+regulatory T cells participate in repair of ischemicacute kidney injury. Kidney Int.76,717–729(2009).
60. Cao, Q. et al. IL-10/TGF-β-modified macrophages induce regulatory T cells andprotect against adriamycin nephrosis. J. Am. Soc. Nephrol.21,933–942(2010).
61. Meran, S.&Steadman, R. Fibroblasts and myofibroblasts in renal fibrosis. Int. J.Exp. Pathol.92,158–167(2011).
62. Grande, M. T.&López-Novoa, J. M. Fibroblast activation and myofibroblastgeneration in obstructive nephropathy. Nat. Rev. Nephrol.5,319–328(2009).
63. Schrimpf, C.&Duffield, J. S. Mechanisms of fibrosis: the role of the pericyte. Curr.Opin. Nephrol. Hypertens.20,297–305(2011).
64. Barnes, J. L.&Gorin, Y. Myofibroblast differentiation during fibrosis: role ofNAD(P)H oxidases. Kidney Int.79,944–956(2011).
65. Hewitson, T. D. Renal tubulointerstitial fibrosis: common but never simple. Am. J.Physiol. Renal Physiol.296, F1239–F1244(2009).
66. Strutz, F.&Zeisberg, M. Renal fibroblasts and myofibroblasts in chronic kidneydisease. J. Am. Soc. Nephrol.17,2992–2998(2006).
67. Paliege, A. et al. Hypoxia-inducible factor-2α-expressing interstitial fibroblasts arethe only renal cells that express erythropoietin under hypoxia-inducible factorstabilization. Kidney Int.77,312–318(2010).
68. Boor, P.&Floege, J. Chronic kidney disease growth factors in renal fibrosis. Clin.Exp. Pharmacol. Physiol.38,391–400(2011).
69. Floege, J., Eitner, F.&Alpers, C. E. A new look at platelet-derived growth factor inrenal disease. J. Am. Soc. Nephrol.19,12–23(2008).
70. Boye, K.&Maelandsmo, G. M. S100A4and metastasis: a small actor playing manyroles. Am. J. Pathol.176,528–535(2010).
71. Grigorian, M., Ambartsumian, N.&Lukanidin, E. Metastasis-inducing S100A4protein: implication in non-malignant human pathologies. Curr. Mol. Med.8,492–496(2008).
72. Wynn, T. A. Common and unique mechanisms regulate fibrosis in variousfibroproliferative diseases. J. Clin. Invest.117,524–529(2007).
73. Hinz, B. et al. The myofibroblast: one function, multiple origins. Am. J. Pathol.170,1807–1816(2007).
74. Lin, S. L., Kisseleva, T., Brenner, D. A.&Duffield, J. S. Pericytes and perivascularfibroblasts are the primary source of collagen-producing cells in obstructive fibrosisof the kidney. Am. J. Pathol.173,1617–1627(2008).
75. Takeji, M. et al. Smooth muscle α-actin deficiency in myofibroblasts leads toenhanced renal tissue fibrosis. J. Biol. Chem.281,40193–40200(2006).
76. Zou, J. et al. Upregulation of nestin, vimentin, and desmin in rat podocytes inresponse to injury. Virchows Arch.448,485–492(2006).
77. Phanish, M. K., Winn, S. K.&Dockrell, M. E. Connective tissue growthfactor-(CTGF, CCN2)—a marker, mediator and therapeutic target for renal fibrosis.Nephron Exp. Nephrol.114, e83–e92(2010).
78. B ttinger, E. P. TGF-β in renal injury and disease. Semin. Nephrol.27,309–320(2007).
79. Strutz, F. et al. Basic fibroblast growth factor expression is increased in human renalfibrogenesis and may mediate autocrine fibroblast proliferation. Kidney Int.57,1521–1538(2000).
80. Ostendorf, T., Eitner, F.&Floege, J. The PDGF family in renal fibrosis. Pediatr.Nephrol. http://dx.doi.org/10.1007/s00467-011-1892-z.
81. Hu, K. et al. tPA protects renal interstitial fibroblasts and myofibroblasts fromapoptosis. J. Am. Soc. Nephrol.19,503–514(2008).
82. Hao, S., Shen, H., Hou, Y., Mars, W. M.&Liu, Y. tPA is a potent mitogen for renalinterstitial fibroblasts: role of β1integrin/focal adhesion kinase. Am. J. Pathol.177,1164–1175(2010).
83. Lin, L. et al. tPA activates LDL receptor-related protein1-mediated mitogenicsignaling involving the p90RSK and GSK3β pathway. Am. J. Pathol.177,1687–1696(2010).
84. Hu, K., Wu, C., Mars, W. M.&Liu, Y. Tissue-type plasminogen activator promotesmurine myofibroblast activation through LDL receptor-related protein1-mediatedintegrin signaling. J. Clin. Invest.117,3821–3832(2007).
85. Hu, K. et al. Tissue-type plasminogen activator acts as a cytokine that triggersintracellularsignal transduction and induces matrix metalloproteinase-9geneexpression. J. Biol. Chem.281,2120–2127(2006).
86. Duffield, J. S.&Humphreys, B. D. Origin of new cells in the adult kidney: resultsfrom genetic labeling techniques. Kidney Int.79,494–501(2011).
87. Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin ofmyofibroblasts in kidney fibrosis. Am. J. Pathol.176,85–97(2010).
88. Kalluri, R.&Weinberg, R. A. The basics of epithelial-mesenchymal transition. J.Clin. Invest.119,1420–1428(2009).
89. Acloque, H., Adams, M. S., Fishwick, K., Bronner-Fraser, M.&Nieto, M. A.Epithelial-mesenchymal transitions: the importance of changing cell state indevelopment and disease. J. Clin. Invest.119,1438–1449(2009).
90. Sleeman, J. P.&Thiery, J. P. SnapShot: the epithelial-mesenchymal transition. Cell145,162.e1(2011).
91. Li, J., Qu, X.&Bertram, J. F. Endothelial-myofibroblast transition contributes to theearly development of diabetic renal interstitial fibrosis in streptozotocin-induceddiabetic mice. Am. J. Pathol.175,1380–1388(2009).
92. Zeisberg, E. M., Potenta, S. E., Sugimoto, H., Zeisberg, M.&Kalluri, R. Fibroblastsin kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc.Nephrol.19,2282–2287(2008).
93. Kriz, W., Kaissling, B.&Le Hir, M. Epithelial-mesenchymal transition (EMT) inkidney fibrosis: fact or fantasy? J. Clin. Invest.121,468–474(2011).
94. Zeisberg, M.&Duffield, J. S. Resolved: EMT produces fibroblasts in the kidney. J.Am. Soc. Nephrol.21,1247–1253(2010).
95. Liu, Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J. Am.Soc. Nephrol.21,212–222(2010).
96. Li, J.&Bertram, J. F. Endothelial-myofibroblast transition, a new player in diabeticrenal fibrosis. Nephrology15,507–512(2010).
97. Burns, W. C.&Thomas, M. C. The molecular mediators of type2epithelial tomesenchymal transition (EMT) and their role in renal pathophysiology. Expert Rev.Mol. Med.12, e17(2010).
98. Grgic, I., Duffield, J. S.&Humphreys, B. D. The origin of interstitialmyofibroblasts in chronic kidney disease. Pediatr. Nephrol. http://dx.doi.org/10.1007/s00467-011-1772-6.
99. Quaggin, S. E.&Kapus, A. Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transition. Kidney Int.80,41–50(2011).
100. Yang, J.&Liu, Y. Dissection of key events in tubular epithelial to myofibroblasttransition and its implications in renal interstitial fibrosis. Am. J. Pathol.159,1465–1475(2001).
101. Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissuefibrosis. J. Clin. Invest.110,341–350(2002).
102. Li, L., Zepeda-Orozco, D., Black, R.&Lin, F. Autophagy is a component ofepithelial cell fate in obstructive uropathy. Am. J. Pathol.176,1767–1778(2010).
103. Togawa, H. et al. Epithelial-to-mesenchymal transition in cyst lining epithelial cellsin an orthologous PCK rat model of autosomal-recessive polycystic kidney disease.Am. J. Physiol. Renal Physiol.300, F511–F520(2011).
104. Boonla, C. et al. Fibrosis and evidence for epithelial-mesenchymal transition in thekidneys of patients with staghorn calculi. BJU Int.108,1336–1345(2011).
105. Yang, J.&Liu, Y. Blockage of tubular epithelial to myofibroblast transition byhepatocyte growth factor prevents renal interstitial fibrosis. J. Am. Soc. Nephrol.13,96–107(2002).
106. Zeisberg, M. et al. BMP-7counteracts TGF-β1-induced epithelial-to-mesenchymaltransition and reverses chronic renal injury. Nat. Med.9,964–968(2003).
107. Hertig, A. et al. Early epithelial phenotypic changes predict graft fibrosis. J. Am. Soc.Nephrol.19,1584–1591(2008).
108. Galichon, P.&Hertig, A. Epithelial to mesenchymal transition as a biomarker inrenal fibrosis: are we ready for the bedside? Fibrogenesis Tissue Repair4,11(2011).
109. He, W. et al. Wnt/β-catenin signaling promotes renal interstitial fibrosis. J. Am. Soc.Nephrol.20,765–776(2009).
110. Li, Y. et al. Inhibition of integrin-linked kinase attenuates renal interstitial fibrosis. J.Am. Soc. Nephrol.20,1907–1918(2009).
111. Yang, J. et al. Disruption of tissue-type plasminogen activator gene in mice reducesrenal interstitial fibrosis in obstructive nephropathy. J. Clin. Invest.110,1525–1538(2002).
112. Liu, Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologicsignificance, molecular mechanism, and therapeutic intervention. J. Am. Soc.Nephrol.15,1–12(2004).
113. Surendran, K., Schiavi, S.&Hruska, K. A. Wnt-dependent β-catenin signaling isactivated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein4alters the progression of renal fibrosis. J. Am. Soc. Nephrol.16,2373–2384(2005).
114. Tan, X., Li, Y.&Liu, Y. Paricalcitol attenuates renal interstitial fibrosis inobstructive nephropathy. J. Am. Soc. Nephrol.17,3382–3393(2006).
115. Zhou, Y. et al. HSP72inhibits Smad3activation and nuclear translocation in renalepithelial-to-mesenchymal transition. J. Am. Soc. Nephrol.21,598–609(2010).
116. Herzog, E. L.&Bucala, R. Fibrocytes in health and disease. Exp. Hematol.38,548–556(2010).
117. Wada, T. et al. Involvement of bone-marrow-derived cells in kidney fibrosis. Clin.Exp. Nephrol.15,8–13(2011).
118. Pilling, D., Fan, T., Huang, D., Kaul, B.&Gomer, R. H. Identification of markersthat distinguish monocyte-derived fibrocytes from monocytes, macrophages, andfibroblasts. PLoS ONE4, e7475(2009).
119. Niedermeier, M. et al. CD4+T cells control the differentiation of Gr1+monocytesinto fibrocytes. Proc. Natl Acad. Sci. USA106,17892–17897(2009).
120. Shao, D. D., Suresh, R., Vakil, V., Gomer, R. H.&Pilling, D. Pivotal Advance: Th-1cytokines inhibit, and Th-2cytokines promote fibrocyte differentiation. J. Leukoc.Biol.83,1323–1333(2008).
121. Sakai, N. et al. The renin-angiotensin system contributes to renal fibrosis throughregulation of fibrocytes. J. Hypertens.26,780–790(2008).
122. Roufosse, C. et al. Bone marrow-derived cells do not contribute significantly tocollagen I synthesis in a murine model of renal fibrosis. J. Am. Soc. Nephrol.17,775–782(2006).
123. Yang, J., Dai, C.&Liu, Y. Hepatocyte growth factor suppresses renal interstitialmyofibroblast activation and intercepts Smad signal transduction. Am. J. Pathol.163,621–632(2003).
124. Schnaper, H. W. et al. TGF-β signal transduction in chronic kidney disease. Front.Biosci.14,2448–2465(2009).
125. Dai, C.&Liu, Y. Hepatocyte growth factor antagonizes the profibrotic action ofTGF-β1in mesangial cells by stabilizing Smad transcriptional corepressor TGIF. J.Am. Soc. Nephrol.15,1402–1412(2004).
126. Liu, Y. Hepatocyte growth factor in kidney fibrosis: therapeutic potential andmechanisms of action. Am. J. Physiol. Renal Physiol.287, F7–F16(2004).
127. Luo, D. D., Phillips, A.&Fraser, D. Bone morphogenetic protein-7inhibitsproximal tubular epithelial cell Smad3signaling via increased SnoN expression. Am.J. Pathol.176,1139–1147(2010).
128. Wang, B. et al. miR-200a prevents renal fibrogenesis through repression of TGF-β2expression. Diabetes60,280–287(2011).
129. Kato, M. et al. A microRNA circuit mediates transforming growth factor-β1autoregulation in renal glomerular mesangial cells. Kidney Int.80,358–368(2011).
130. Inui, M., Martello, G.&Piccolo, S. MicroRNA control of signal transduction. Nat.Rev. Mol. Cell Biol.11,252–263(2010).
131. Chung, A. C., Huang, X. R., Meng, X.&Lan, H. Y. miR-192mediatesTGF-β/Smad3-driven renal fibrosis. J. Am. Soc. Nephrol.21,1317–1325(2010).
132. Zhou, Q. et al. TGF-β-induced MiR-491-5p expression promotes Par-3degradationin rat proximal tubular epithelial cells. J. Biol. Chem.285,40019–40027(2010).
133. Eyden, B. Fibronexus junctions associated with in vivo human endothelium.Ultrastruct. Pathol.33,28–32(2009).
134. Margadant, C.&Sonnenberg, A. Integrin-TGF-β crosstalk in fibrosis, cancer andwound healing. EMBO Rep.11,97–105(2010).
135. Legate, K. R.&F ssler, R. Mechanisms that regulate adaptor binding to β-integrincytoplasmic tails. J. Cell Sci.122,187–198(2009).
136. Legate, K. R., Monta ez, E., Kudlacek, O.&F ssler, R. ILK, PINCH and parvin:the tIPP of integrin signalling. Nat. Rev. Mol. Cell Biol.7,20–31(2006).
137. Maydan, M. et al. Integrin-linked kinase is a functional Mn2+-dependent proteinkinase that regulates glycogen synthase kinase-3β (GSK-3β) phosphorylation. PLoSONE5, e12356(2010).
138. Fukuda, K., Gupta, S., Chen, K., Wu, C.&Qin, J. The pseudoactive site of ILK isessential for its binding to α-parvin and localization to focal adhesions. Mol. Cell36,819–830(2009).
139. He, W. et al. Plasminogen activator inhibitor-1is a transcriptional target of thecanonical pathway of Wnt/β-catenin signaling. J. Biol. Chem.285,24665–24675(2010).
140. ten Berge, D. et al. Wnt signaling mediates self-organization and axis formation inembryoid bodies. Cell Stem Cell3,508–518(2008).
141. Wu, C. PINCH, N(i)ck and the ILK: network wiring at cell-matrix adhesions. TrendsCell Biol.15,460–466(2005).
142. Li, Y., Dai, C., Wu, C.&Liu, Y. PINCH-1promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase. J. Am. Soc.Nephrol.18,2534–2543(2007).
143. Guo, L.&Wu, C. Regulation of fibronectin matrix deposition and cell proliferationby the PINCH–ILK–CH–ILKBP complex. FASEB J.16,1298–1300(2002).
144. Yeh, Y. C. et al. Transforming growth factor-β1induces Smad3-dependent β1integrin gene expression in epithelial-to-mesenchymaltransition during chronictubulointerstitial fibrosis. Am. J. Pathol.177,1743–1754(2010).
145. Li, Y., Yang, J., Dai, C., Wu, C.&Liu, Y. Role for integrin-linked kinase inmediating tubular epithelial to mesenchymal transition and renal interstitialfibrogenesis. J. Clin. Invest.112,503–516(2003).
146. Liu, X. C., Liu, B. C., Zhang, X. L., Li, M. X.&Zhang, J. D. Role of ERK1/2andPI3-K in the regulation of CTGF-induced ILK expression in HK-2cells. Clin. Chim.Acta382,89–94(2007).
147. Han, S. Y. et al. High glucose and angiotensin II increase β1integrin andintegrin-linked kinase synthesis in cultured mouse podocytes. Cell Tissue Res.323,321–332(2006).
148. Yang, F. et al. Essential role for Smad3in angiotensin II-induced tubularepithelial-mesenchymal transition. J. Pathol.221,390–401(2010).
149. Carvajal, G. et al. Angiotensin II activates the Smad pathway during epithelialmesenchymal transdifferentiation. Kidney Int.74,585–595(2008).
150. Yang, F., Chung, A. C., Huang, X. R.&Lan, H. Y. Angiotensin II inducesconnective tissue growth factor and collagen I expression via transforming growthfactor-β-dependent and-independent Smad pathways: the role of Smad3.Hypertension54,877–884(2009).
151. Eddy, A. A. Progression in chronic kidney disease. Adv. Chronic Kidney Dis.12,353–365(2005).
152. Bradshaw, A. D. The role of SPARC in extracellular matrix assembly. J. CellCommun. Signal.3,239–246(2009).
153. Weaver, M. S., Workman, G.&Sage, E. H. The copper binding domain of SPARCmediates cell survival in vitro via interaction with integrin β1and activation ofintegrin-linked kinase. J. Biol. Chem.283,22826–22837(2008).
154. Shweke, N. et al. Tissue transglutaminase contributes to interstitial renal fibrosis byfavoring accumulation of fibrillar collagen through TGF-β activation and cellinfiltration. Am. J. Pathol.173,631–642(2008).
155. Huang, L. et al. Transglutaminase inhibition ameliorates experimental diabeticnephropathy. Kidney Int.76,383–394(2009).
156. He, W., Kang, Y. S., Dai, C.&Liu, Y. Blockade of Wnt/β-catenin signaling byparicalcitol ameliorates proteinuria and kidney injury. J. Am. Soc. Nephrol.22,90–103(2011).
157. Sharma, S., Sirin, Y.&Susztak, K. The story of Notch and chronic kidney disease.Curr. Opin. Nephrol. Hypertens.20,56–61(2011).
158. Bielesz, B. et al. Epithelial Notch signaling regulates interstitial fibrosisdevelopment in the kidneys of mice and humans. J. Clin. Invest.120,4040–4054(2010).
159. Higgins, D. F. et al. Hypoxia promotes fibrogenesis in vivo via HIF-1stimulation ofepithelial-to-mesenchymal transition. J. Clin. Invest.117,3810–3820(2007).
160. Sun, S. et al. Hypoxia-inducible factor-1α induces Twist expression in tubularepithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition.Kidney Int.75,1278–1287(2009).
161. Kume, S. et al. Calorie restriction enhances cell adaptation to hypoxia throughSirt1-dependent mitochondrial autophagy in mouse aged kidney. J. Clin. Invest.120,1043–1055(2010).
162. Jiang, M., Liu, K., Luo, J.&Dong, Z. Autophagy is a renoprotective mechanismduring in vitro hypoxia and in vivo ischemia-reperfusion injury. Am. J. Pathol.176,1181–1192(2010).
163. Koesters, R. et al. Tubular overexpression of transforming growth factor-β1inducesautophagy and fibrosis but not mesenchymal transition of renal epithelialcells. Am. J. Pathol.177,632–643(2010).
164. Yang, L., Besschetnova, T. Y., Brooks, C. R., Shah, J. V.&Bonventre, J. V.Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat. Med.16,535–543(2010).
165. Wang, S. et al. Renal bone morphogenetic protein-7protects against diabeticnephropathy. J. Am. Soc. Nephrol.17,2504–2512(2006).
166. Tan, X., He, W.&Liu, Y. Combination therapy with paricalcitol and trandolaprilreduces renal fibrosis in obstructive nephropathy. Kidney Int.76,1248–1257(2009).
167. de Zeeuw, D. et al. Selective vitamin D receptor activation with paricalcitol forreduction of albuminuria in patients with type2diabetes (VITAL study): arandomised controlled trial. Lancet376,1543–1551(2010).
168. Mirkovic, K., van den Born, J., Navis, G.&de Borst, M. H. Vitamin D in chronickidney disease: new potential for intervention. Curr. Drug Targets12,42–53(2011).
169. Wang, X. et al. Mice lacking the matrix metalloproteinase-9gene reduce renalinterstitial fibrosis in obstructive nephropathy. Am. J. Physiol. Renal Physiol.299,F973–F982(2010).
170. Cheng, S., Pollock, A. S., Mahimkar, R., Olson, J. L.&Lovett, D. H. Matrixmetalloproteinase2and basement membrane integrity: a unifying mechanism forprogressive renal injury. FASEB J.20,1898–1900(2006).
171. Zeisberg, M. et al. Stage-specific action of matrix metalloproteinases influencesprogressive hereditary kidney disease. PLoS Med.3, e100(2006).
172. Li, J. et al. Blockade of endothelial-mesenchymal transition by a Smad3inhibitordelays the early development of streptozotocin-induced diabetic nephropathy.Diabetes59,2612–2624(2010).
173. Lin, S. L. et al. Targeting endothelium-pericyte cross talk by inhibiting VEGFreceptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am. J.Pathol.178,911–923(2011).
174. Venkatachalam, M. A. et al. Acute kidney injury: a springboard for progression inchronic kidney disease. Am. J. Physiol. Renal Physiol.298, F1078–F1094(2010).
175. Kelly, K. J., Burford, J. L.&Dominguez, J. H. Postischemic inflammatorysyndrome: a critical mechanism of progression in diabetic nephropathy. Am. J.Physiol. Renal Physiol.297, F923–F931(2009).
176. Guo, Z. J. et al. Advanced oxidation protein products activate vascular endothelialcells via a RAGE-mediated signaling pathway. Antioxid. Redox Signal.10,1699–1712(2008).
177. Wilkinson, L. et al. Loss of renal microvascular integrity in postnatal Crim1hypomorphic transgenic mice. Kidney Int.76,1161–1171(2009).
178. Mimura, I.&Nangaku, M. The suffocating kidney: tubulointerstitial hypoxia inend-stage renal disease. Nat. Rev. Nephrol.6,667–678(2010).
179. Touyz, R. M.&Briones, A. M. Reactive oxygen species and vascular biology:implications in human hypertension. Hypertens. Res.34,5–14(2011).
180. Fine, L. G.&Norman, J. T. Chronic hypoxia as a mechanism of progression ofchronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int.74,867–872(2008).
181. Gunaratnam, L.&Bonventre, J. V. HIF in kidney disease and development. J. Am.Soc. Nephrol.20,1877–1887(2009).
182. D’Agati, V.&Schmidt, A. M. RAGE and the pathogenesis of chronic kidney disease.Nat. Rev. Nephrol.6,352–360(2010).
183. Negre-Salvayre, A., Coatrieux, C., Ingueneau, C.&Salvayre, R. Advanced lipidperoxidation end products in oxidative damage to proteins. Potential role in diseasesand therapeutic prospects for the inhibitors. Br. J. Pharmacol.153,6–20(2008).
184. Zhou, L. L. et al. Accumulation of advanced oxidation protein products inducespodocyte apoptosis and deletion through NADPH-dependent mechanisms. KidneyInt.76,1148–1160(2009).
185. Shi, X. Y. et al. Advanced oxidation protein products promote inflammation indiabetic kidney through activation of renal nicotinamide adenine dinucleotidephosphate oxidase. Endocrinology149,1829–1839(2008).
186. Daroux, M. et al. Advanced glycation end-products: implications for diabetic andnon-diabetic nephropathies. Diabetes Metab.36,1–10(2010).
187. Shanmugam, N. et al. Proinflammatory effects of advanced lipoxidation endproducts in monocytes. Diabetes57,879–888(2008).
188. Bechtel, W. et al. Methylation determines fibroblast activation and fibrogenesis inthe kidney. Nat. Med.16,544–550(2010).
189. Hu, K., Mars, W. M.&Liu, Y. Novel actions of tissue-type plasminogen activator inchronic kidney disease. Front. Biosci.13,5174–5186(2008).