Notch1/Jagged1在肾间质纤维化发病机制中的作用及干预的研究
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摘要
背景:
无论肾脏病原发病因和部位在肾小球、肾小管还是肾血管,最终均可导致肾小管萎缩和消失、肾间质增生和纤维化,肾功能的损害都与肾脏纤维化病变的程度密切相关。这些疾病能引起肾小管上皮细胞的凋亡、肾间质炎性细胞的浸润、肌成纤维细胞的聚集,并在一些促纤维化因子的参与下,使细胞外基质(ECM)生成增多、降解减少,而产生肾间质纤维化,导致肾功能严重受损。围绕小管间质损伤后的间质纤维化发生发展机理和防治方面的研究受到广泛重视,已知有多种信号通路和细胞因子涉及肾间质纤维化的发生发展,目前研究集中于肾间质纤维化发生机制可能与多种细胞(如肾小管上皮细胞、间质成纤维细胞等)转变或转分化(上皮细胞转分化,EMT)为肌成纤维细胞(MyoFB),其中TGF-β1可能是主要的致纤维化细胞因子之一,导致EMT和细胞激活。而Notch信号通路参与组织发育和损伤修复,可能与TGF-β信号通路存在相互反应,可能参与肾间质纤维化。为证实我们的推测,设计了以下几个方面的研究。
目的:
1.阐明在整体条件下,Notchl/Jaggedl信号通路是否在大鼠单侧输尿管梗阻后肾间质纤维化起重要作用并研究雷帕霉素对肾间质纤维化的调节作用。
2.探讨用RNA干扰(RNAi)抑制Jaggedl对Notchl/Jaggedl信号改变在肾间质成纤维细胞分泌致纤维化因子的作用。
3.研究雷帕霉素和丹酚酸B盐在体外是否调节Notchl/Jaggedl信号通路介导抗纤维化的作用机制。
BackgroundCommon diseases causing progressive chronic renal failure, whatever the initiating injury are associated with fibrosis. Although these chronic tubulointerstitial changes have long been known to closely parallel a decline in renal function, and to have prognostic significance, their genesis and role in progression have received little attention until relatively recently. Over the past few years interest, initially focused on glomerular sclerosis as the major factor in progressive renal failure, has shifted towards the pathogenesis and role of tubulointerstitial changes in renal functional decline, and accordingly to whether interference with the mechanisms may be one way of slowing renal functional deterioration. Tubulointerstitial fibrosis is the final common pathway to end-stage renal disease.Understanding the mechanisms of tubulointerstitial fibrosis is essential in establishing novel therapeutic strategies for the prevention or arrest of progressive kidney diseases. Inflammation of the tubulointerstitial compartment, leading to fibrosis, is a major factor in the progressive loss of renal function in patients with a wide variety of kidney diseases. About 80% of the total kidney is composed of tubule epithelial cells and cells within the interstitial space. Most of the nonepithelial cells are associated with the rich vascular network of the kidney. There are also a small number of resident mononuclear cells and fibroblasts. A model of renal fibrosis that encompasses many aspects of other models of kidney disease is unilateral ureteral obstruction (UUO). Recent studies indicate that transforming growth factor-β (TGF-β) is linked to many of the cellular and molecular changes of renal tubulointerstitial fibrosis, one that emphasizes the
roles of epithelial-mesenchymal transition (EMT) and cellular activation.Irrespective of the initial causes, interstitial fibrosis is a remarkably monotonous process characterized by de novo activation of a-smooth muscle actin (a-SMA)-positive myofibroblasts, the principal effecter cells that are responsible for the excess deposition of interstitial ECM under pathologic conditions. In this sense, a possible key to an effective therapy for CKD is to find a strategy that inhibits the activation of renal myofibroblasts in diseased kidney. Similarly, several studies have indicated that administration of renotrophic factors, such as insulin-like growth factor, hepatocyte growth factor, and bone morphogenic protein-7, can ameliorate fibrotic kidney disease.Tubular EMT, by definition, is a process in which renal tubular cells lose their epithelial phenotype and acquire new characteristic features of mesenchyme. This model of EMT process is largely based on detailed studies of phenotypic alterations in cultured tubular epithelial cells after stimulation with TGF-β1 and in renal tubular epithelia after obstructive injury. Despite that, it only represents an initial attempt to understand the complex process of EMT and is certainly subjected to any modifications. Nevertheless, it appears clear that EMT is an orchestrated process that depends on many intricate interactions between extrinsic regulators and intracellular mediators. EMT is regulated by numerous growth factors, cytokines, hormones, and extracellular cues in different ways. Of the many factors identified, the chief one perhaps is profibrotic TGF-β1. Induction of EMT may be a major pathway of TGF-β1 that leads to interstitial fibrosis under pathologic conditions.Notch signaling is a highly conserved mechanism used by multicellular animals to specify cell fate decisions during the formation of complex structures such as the kidney. A number of
studies have recently identified requirements for Notch signaling during kidney organogenesis and tissue repair. A recent microarray survey of transcriptional changes in human keratinocytes exposed to TGF-β1 identified several components of the Notch pathway, including the basic helix-loop-helix transcription factor Hes-1 and Hey-1, a direct target of Notch signaling.To more fully unde
无论肾脏病原发病因和部位在肾小球、肾小管还是肾血管,最终均可导致肾小管萎缩和消失、肾间质增生和纤维化,肾功能的损害都与肾脏纤维化病变的程度密切相关。这些疾病能引起肾小管上皮细胞的凋亡、肾间质炎性细胞的浸润、肌成纤维细胞的聚集,并在一些促纤维化因子的参与下,使细胞外基质(ECM)生成增多、降解减少,而产生肾间质纤维化,导致肾功能严重受损。围绕小管间质损伤后的间质纤维化发生发展机理和防治方面的研究受到广泛重视,已知有多种信号通路和细胞因子涉及肾间质纤维化的发生发展,目前研究集中于肾间质纤维化发生机制可能与多种细胞(如肾小管上皮细胞、间质成纤维细胞等)转变或转分化(上皮细胞转分化,EMT)为肌成纤维细胞(MyoFB),其中TGF-β1可能是主要的致纤维化细胞因子之一,导致EMT和细胞激活。而Notch信号通路参与组织发育和损伤修复,可能与TGF-β信号通路存在相互反应,可能参与肾间质纤维化。为证实我们的推测,设计了以下几个方面的研究。
目的:
1.阐明在整体条件下,Notchl/Jaggedl信号通路是否在大鼠单侧输尿管梗阻后肾间质纤维化起重要作用并研究雷帕霉素对肾间质纤维化的调节作用。
2.探讨用RNA干扰(RNAi)抑制Jaggedl对Notchl/Jaggedl信号改变在肾间质成纤维细胞分泌致纤维化因子的作用。
3.研究雷帕霉素和丹酚酸B盐在体外是否调节Notchl/Jaggedl信号通路介导抗纤维化的作用机制。
BackgroundCommon diseases causing progressive chronic renal failure, whatever the initiating injury are associated with fibrosis. Although these chronic tubulointerstitial changes have long been known to closely parallel a decline in renal function, and to have prognostic significance, their genesis and role in progression have received little attention until relatively recently. Over the past few years interest, initially focused on glomerular sclerosis as the major factor in progressive renal failure, has shifted towards the pathogenesis and role of tubulointerstitial changes in renal functional decline, and accordingly to whether interference with the mechanisms may be one way of slowing renal functional deterioration. Tubulointerstitial fibrosis is the final common pathway to end-stage renal disease.Understanding the mechanisms of tubulointerstitial fibrosis is essential in establishing novel therapeutic strategies for the prevention or arrest of progressive kidney diseases. Inflammation of the tubulointerstitial compartment, leading to fibrosis, is a major factor in the progressive loss of renal function in patients with a wide variety of kidney diseases. About 80% of the total kidney is composed of tubule epithelial cells and cells within the interstitial space. Most of the nonepithelial cells are associated with the rich vascular network of the kidney. There are also a small number of resident mononuclear cells and fibroblasts. A model of renal fibrosis that encompasses many aspects of other models of kidney disease is unilateral ureteral obstruction (UUO). Recent studies indicate that transforming growth factor-β (TGF-β) is linked to many of the cellular and molecular changes of renal tubulointerstitial fibrosis, one that emphasizes the
roles of epithelial-mesenchymal transition (EMT) and cellular activation.Irrespective of the initial causes, interstitial fibrosis is a remarkably monotonous process characterized by de novo activation of a-smooth muscle actin (a-SMA)-positive myofibroblasts, the principal effecter cells that are responsible for the excess deposition of interstitial ECM under pathologic conditions. In this sense, a possible key to an effective therapy for CKD is to find a strategy that inhibits the activation of renal myofibroblasts in diseased kidney. Similarly, several studies have indicated that administration of renotrophic factors, such as insulin-like growth factor, hepatocyte growth factor, and bone morphogenic protein-7, can ameliorate fibrotic kidney disease.Tubular EMT, by definition, is a process in which renal tubular cells lose their epithelial phenotype and acquire new characteristic features of mesenchyme. This model of EMT process is largely based on detailed studies of phenotypic alterations in cultured tubular epithelial cells after stimulation with TGF-β1 and in renal tubular epithelia after obstructive injury. Despite that, it only represents an initial attempt to understand the complex process of EMT and is certainly subjected to any modifications. Nevertheless, it appears clear that EMT is an orchestrated process that depends on many intricate interactions between extrinsic regulators and intracellular mediators. EMT is regulated by numerous growth factors, cytokines, hormones, and extracellular cues in different ways. Of the many factors identified, the chief one perhaps is profibrotic TGF-β1. Induction of EMT may be a major pathway of TGF-β1 that leads to interstitial fibrosis under pathologic conditions.Notch signaling is a highly conserved mechanism used by multicellular animals to specify cell fate decisions during the formation of complex structures such as the kidney. A number of
studies have recently identified requirements for Notch signaling during kidney organogenesis and tissue repair. A recent microarray survey of transcriptional changes in human keratinocytes exposed to TGF-β1 identified several components of the Notch pathway, including the basic helix-loop-helix transcription factor Hes-1 and Hey-1, a direct target of Notch signaling.To more fully unde
引文
1. Eddy AA. Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol. 1996, 7: 2495-2508.
2. Strutz F, Muller GA. Interstitial pathomechanisms underlying progressive tubulointerstitial damage. Kidney Blood Pres Res. 1999, 22: 67-75.
3. Gavin J Becker, Tim D Hewitson. The role of tubulointerstitial injury in chronic renal failure. Curr OpinNephrol Hypertens. 2000, 9: 133-138.
4. O'Donnell MP. Renal tubulointerstitial fibrosis. New thoughts on its development and progression. Postgrad Med J. 2000, 108: 159-162.
5. Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol. 2000, 15: 290-301.
6. Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis. Am J Physiol Renal Physiol. 2002, 283: F861-875.
7. Iwano M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. Curr Opin Nephrol Hypertens. 2004, 13: 279-284.
8. Philippe Reisdorf, David A. Lawrence, Virginie Sivan, et al. Alteration of transforming growth factor-β1 response involves down-regulation of Smad3 signaling in myofibroblasts from skin fibrosis. Am J Pathol. 2001, 159: 263-272.
9. C. Hill, A. Flyvbjerg, H. Gr(?)nb(?)k, et al. The renal expression of transforming growth factor-β isoforms and their receptors in acute and chronic experimental diabetes in rats. Endocrinology. 2000, 141: 1196-1208.
10. Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med. 2004, 82: 175-181.
11. Schnaper HW, Hayashida T, Hubchak SC, et al. TGF-beta signal transduction and mesangial cell fibrogenesis. Am J Physiol Renal Physiol. 2003, 284: F243-252.
12. Bottinger EP, Bitzer M. TGF-beta Signaling in Renal Disease. J Am Soc Nephrol. 2002, 13: 2600-2610.
13. Yang JW, Liu YH. Dissection of key events in tubularepithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001, 159: 1465-1475.
14. Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol. 2004, 15: 1-12.
15. Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat. 1995, 154: 8-20.
16. Hay ED, Zuk A. Transformations between epithelium and mesenchyme : normal , pathological , and experimentally induced. Am J Kidney Disease. 1995, 26: 678-690.
17. Fan JM, Huang XR , Ng YY, et al. Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta-dependent mechanism in vitro. Am J Kidney Disease. 2001, 38:820-831.
18. HY Lan. Tubular epithelial - myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr OpinNephrol Hypertens. 2003, 12: 25-29.
19. Cheng Sunfa, David H Lovett . Gelatinase A (MMP - 2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol. 2003, 162: 1937-1949.
20. Yingjian Li, Junwei Yang, Chunsun Dai, et al. Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J Clin Invest. 2004, 113: 491.
21. Junwei Yang, Xianghong Zhang, Yingjian Li, et al. Downregulation of Smad transcriptional corepressors SnoN and Ski in the fibrotic Kidney: an amplification mechanism for TGF-β1 signaling. J Am Soc Nephrol. 2003, 14:3167-3177.
22. Junwei Yang, Chunsun Dai, Youhua Liu ,et al. Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction. Am J Pathol. 2003, 163: 621-632.
23. Boettner B, L Van Aelst. The role of Rho GTPases in disease development . Gene. 2002, 286: 155-174.
24. Blom IE, A J van Dijk, R A de Weger, et al. Identification of human ccn2 (connective tissue growth factor) promoter polymorphisms. Mol Pathol. 2001,54: 192-196.
25. Yokoi H, Mukoyama M, Sugawara A, et al. Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis. Am J Physiol Renal Physiol. 2002, 282: F933-942.
26. Andras Masszi, Caterina Di Ciano, Gabor Sirokmany, et al. Central role for Rho in TGF-beta12 induced alpha-smooth muscle actin expression during epithelial-mesenchymal transition. Am J Physiol Renal Physiol. 2003, 284: F911-924.
27. Ya-Chung Tian, Donald Fraser, Liliana Attisano, et al. TGF- β1-mediated alterations of renal proximal tubular epithelial cell phenotype. Am J Physiol Renal Physiol. 2003, 285: 130-142.
28. K Nagatoya, T Moriyama, N Kawada, et al. Y227632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction. Kidney Int. 2002, 61: 1684-1695.
29. S Satoh, T Yamaguchi, A Hitomi, et al. Fasudil attenuates interstitial fibrosis in rat kidneys with unilateral ureteral obstruction. Eur J Pharmacol. 2002, 455:169-174.
30. Artavanis-Tsakonas SR, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999, 284: 770-776.
31. Nam Y, Weng A P, Aster J C, et al. Structural requirements for assembly of the CSL intracellular Notchl Mastermind-like 1 transcriptional activation complex. J Biol Chem. 2003, 278: 21232-21239.
32. Iso T, Kedes L, Hamamori Y. HES , HERP families: Multiple effectors of the notch signaling pathway. J Cell Physiol. 2003, 194: 237-255.
33. Politi K, Feirt N, Kitajewski J. Notch in mammary gland development and breast cancer. Semin Cancer Biol. 2004, 14: 341-347.
34. Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003, 422: 438-441.
35. Politi K, Feirt N, Kitajewski J. Notch in mammary gland development and breast cancer. Semin Cancer Biol. 2004, 14: 341-347.
36. McCright B. Notch signaling in kidney development. Curr Opin Nephrol Hypertens. 2003, 12:5-10.
37. Morrissey J, Guo G, Moridaira K, et al. Transforming growth factor-β induces renal epithelial Jagged-1 expression in fibrotic disease. J Am Soc Nephrol. 2002, 13: 1499-1508.
38. Blokzijl A, Dahlqvist C, Reissmann E, et al. Cross talk between the Notch and TGF-β signaling pathways mediated by interaction of the Notch intracellular domain with Smad. J Cell Biol. 2003, 163:723-728.
39. Lan HY, Mu W, Tomita N, et al. Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. J Am Soc Nephrol. 2003, 14: 1535-1548.
40. Zeisberg M, Hanai J, Sugimoto H, et al. BMP-7 counteracts TGF-betal induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med. 2003, 9: 964-968.
2. Strutz F, Muller GA. Interstitial pathomechanisms underlying progressive tubulointerstitial damage. Kidney Blood Pres Res. 1999, 22: 67-75.
3. Gavin J Becker, Tim D Hewitson. The role of tubulointerstitial injury in chronic renal failure. Curr OpinNephrol Hypertens. 2000, 9: 133-138.
4. O'Donnell MP. Renal tubulointerstitial fibrosis. New thoughts on its development and progression. Postgrad Med J. 2000, 108: 159-162.
5. Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol. 2000, 15: 290-301.
6. Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis. Am J Physiol Renal Physiol. 2002, 283: F861-875.
7. Iwano M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. Curr Opin Nephrol Hypertens. 2004, 13: 279-284.
8. Philippe Reisdorf, David A. Lawrence, Virginie Sivan, et al. Alteration of transforming growth factor-β1 response involves down-regulation of Smad3 signaling in myofibroblasts from skin fibrosis. Am J Pathol. 2001, 159: 263-272.
9. C. Hill, A. Flyvbjerg, H. Gr(?)nb(?)k, et al. The renal expression of transforming growth factor-β isoforms and their receptors in acute and chronic experimental diabetes in rats. Endocrinology. 2000, 141: 1196-1208.
10. Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med. 2004, 82: 175-181.
11. Schnaper HW, Hayashida T, Hubchak SC, et al. TGF-beta signal transduction and mesangial cell fibrogenesis. Am J Physiol Renal Physiol. 2003, 284: F243-252.
12. Bottinger EP, Bitzer M. TGF-beta Signaling in Renal Disease. J Am Soc Nephrol. 2002, 13: 2600-2610.
13. Yang JW, Liu YH. Dissection of key events in tubularepithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001, 159: 1465-1475.
14. Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol. 2004, 15: 1-12.
15. Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat. 1995, 154: 8-20.
16. Hay ED, Zuk A. Transformations between epithelium and mesenchyme : normal , pathological , and experimentally induced. Am J Kidney Disease. 1995, 26: 678-690.
17. Fan JM, Huang XR , Ng YY, et al. Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta-dependent mechanism in vitro. Am J Kidney Disease. 2001, 38:820-831.
18. HY Lan. Tubular epithelial - myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr OpinNephrol Hypertens. 2003, 12: 25-29.
19. Cheng Sunfa, David H Lovett . Gelatinase A (MMP - 2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol. 2003, 162: 1937-1949.
20. Yingjian Li, Junwei Yang, Chunsun Dai, et al. Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J Clin Invest. 2004, 113: 491.
21. Junwei Yang, Xianghong Zhang, Yingjian Li, et al. Downregulation of Smad transcriptional corepressors SnoN and Ski in the fibrotic Kidney: an amplification mechanism for TGF-β1 signaling. J Am Soc Nephrol. 2003, 14:3167-3177.
22. Junwei Yang, Chunsun Dai, Youhua Liu ,et al. Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction. Am J Pathol. 2003, 163: 621-632.
23. Boettner B, L Van Aelst. The role of Rho GTPases in disease development . Gene. 2002, 286: 155-174.
24. Blom IE, A J van Dijk, R A de Weger, et al. Identification of human ccn2 (connective tissue growth factor) promoter polymorphisms. Mol Pathol. 2001,54: 192-196.
25. Yokoi H, Mukoyama M, Sugawara A, et al. Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis. Am J Physiol Renal Physiol. 2002, 282: F933-942.
26. Andras Masszi, Caterina Di Ciano, Gabor Sirokmany, et al. Central role for Rho in TGF-beta12 induced alpha-smooth muscle actin expression during epithelial-mesenchymal transition. Am J Physiol Renal Physiol. 2003, 284: F911-924.
27. Ya-Chung Tian, Donald Fraser, Liliana Attisano, et al. TGF- β1-mediated alterations of renal proximal tubular epithelial cell phenotype. Am J Physiol Renal Physiol. 2003, 285: 130-142.
28. K Nagatoya, T Moriyama, N Kawada, et al. Y227632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction. Kidney Int. 2002, 61: 1684-1695.
29. S Satoh, T Yamaguchi, A Hitomi, et al. Fasudil attenuates interstitial fibrosis in rat kidneys with unilateral ureteral obstruction. Eur J Pharmacol. 2002, 455:169-174.
30. Artavanis-Tsakonas SR, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999, 284: 770-776.
31. Nam Y, Weng A P, Aster J C, et al. Structural requirements for assembly of the CSL intracellular Notchl Mastermind-like 1 transcriptional activation complex. J Biol Chem. 2003, 278: 21232-21239.
32. Iso T, Kedes L, Hamamori Y. HES , HERP families: Multiple effectors of the notch signaling pathway. J Cell Physiol. 2003, 194: 237-255.
33. Politi K, Feirt N, Kitajewski J. Notch in mammary gland development and breast cancer. Semin Cancer Biol. 2004, 14: 341-347.
34. Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003, 422: 438-441.
35. Politi K, Feirt N, Kitajewski J. Notch in mammary gland development and breast cancer. Semin Cancer Biol. 2004, 14: 341-347.
36. McCright B. Notch signaling in kidney development. Curr Opin Nephrol Hypertens. 2003, 12:5-10.
37. Morrissey J, Guo G, Moridaira K, et al. Transforming growth factor-β induces renal epithelial Jagged-1 expression in fibrotic disease. J Am Soc Nephrol. 2002, 13: 1499-1508.
38. Blokzijl A, Dahlqvist C, Reissmann E, et al. Cross talk between the Notch and TGF-β signaling pathways mediated by interaction of the Notch intracellular domain with Smad. J Cell Biol. 2003, 163:723-728.
39. Lan HY, Mu W, Tomita N, et al. Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. J Am Soc Nephrol. 2003, 14: 1535-1548.
40. Zeisberg M, Hanai J, Sugimoto H, et al. BMP-7 counteracts TGF-betal induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med. 2003, 9: 964-968.