从HIF-1信号通路探讨六味地黄汤干预5/6肾切除大鼠肾间质纤维化实验研究
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摘要
目的：观察六味地黄汤对5/6肾切除大鼠肾间质纤维化的影响,从HIF-1信号通路探讨其作用机制。
方法：80只健康雄性SD大鼠随机分成空白对照组、假手术组、模型组、六味地黄汤组和依那普利组。采用5/6肾切除法复制肾间质纤维化动物模型,造模12周后处死动物,收集大鼠尿液检测24h尿蛋白,腹主动脉采血检测血尿素氮(BUN)和血清肌酐(SCr)水平,观察肾功能变化；HE、Masson染色观察大鼠肾组织形态学改变；免疫组化、ⅤVestern blot法检测Ⅰ型胶原(Col Ⅰ)、Ⅲ型胶原(ColⅢ)、纤维连接蛋白(FN)蛋白表达水平,观察肾组织细胞外基质积聚的情况；免疫组化、Western blot.RT-PCR法检测肾组织缺氧诱导因子1α (HIF-1α).结缔组织生长因子(CTGF)、血浆纤溶酶原激活物抑制物-1(PAI-1)、金属基质蛋白酶组织抑制因子-1(TIMP-1)蛋白及mRNA的表达,观察HIF-1信号通路对肾间质纤维化的影响。
结果：
1、六味地黄汤能降低5/6肾切除12周后大鼠24h尿蛋白,能降低BUN和SCr水平,能减轻大鼠肾组织肾小球硬化、肾小管萎缩及间质纤维化程度,具有保护和修复肾脏组织的作用。
2、六味地黄汤能降低5/6肾切除12周后大鼠肾组织中ColⅠ、ColⅢ、 FN蛋白表达水平,具有改善细胞外基质积聚的作用。
3、六味地黄汤能降低5/6肾切除12周后大鼠肾组织HIF-1α、 CTGF、PAI-1、TIMP-1蛋白及：mRNA表达水平,具有下调HIF-1信号通路,延缓肾间质纤维化的作用。
结论：六味地黄汤能改善晚期肾间质纤维化大鼠肾功能、减轻肾脏组织形态变化及减少细胞外基质的积聚,其作用机制可能通过抑制HIF-1信号通路,因而明确了其抗肾间质纤维化的作用机制,同时HIF-1α可作为抗肾间质纤维化治疗的新靶点。
Objective:To observe the effect of Liuweidihuang Decoction on renal interstitial fibrosis in rats with5/6nephrectomy, and to explore its mechanism from the HIF-1signal pathway.
Methods:Eighty healthy male Sprapue-Demey rats were randomly divided into blank control group, sham operation group, model group, Liuweidihuang Decoction group and enalapril group. The method of5/6nephrectomy was used to construct animal model of renal interstitial fibrosis. Rats were killed after12weeks, urine and abdominal aortic blood were collected to test24h urine protein, BUN and SCr respectively, which to monitor the changes of renal function. HE and Masson staining methods were used to observe the morphological changes of the renal tissues in rats. Immunohistochemistry and Western blot method were used to detect expression level of Col I, Col III and FN protein, which to observe the deposition of extracellular matrix. Immunohistochemistry, Western blot and RT-PCR methods were used to detection of expression levels of HIF-1a, CTGF, PAI-1and TIMP-1, which to observe the effect of HIF-1signal pathway on renal interstitial fibrosis.
Result:
1. Liuweidihuang Decoction can reduce24h urine protein, BUN and SCr levels in rats with5/6nephrectomy after12weeks. It also can attenuate the renal tissue of rats with glomerulosclerosis, tubular atrophy and interstitial fibrosis. Liuweidihuang Decoction has the function of protect and restore kidney.
2. After12weeks, Liuweidihuang Decoction decrease expression levels of Col I, Col Ⅲand FN protein in rats renal tissue with5/6nephrectomy, and it also can inhibit the deposition of extracellular matrix.
3. Liuweidihuang Decoction can reduce the expression protein and mRNA levels of HIF-1α, CTGF, PAI-1, TIMP-1in rats renal tissue with5/6nephrectomy after12weeks. It has the role for down-regulating HIF-1signaling pathway and delaying the interstitial fibrosis of renal.
Conclusion:Liuweidihuang Decoction can improve renal interstitial fibrosis of kidney function, relieve pathological advancement of renal tissue and inhibit the extracellular matrix accumulation, and its mechanism of renal interstitial fibrosis may be correlated with down-regulation of HIF-1signaling pathway. Our results suggest HIF-1α can be used as a new target of renal interstitial fibrosis therapy.
方法：80只健康雄性SD大鼠随机分成空白对照组、假手术组、模型组、六味地黄汤组和依那普利组。采用5/6肾切除法复制肾间质纤维化动物模型,造模12周后处死动物,收集大鼠尿液检测24h尿蛋白,腹主动脉采血检测血尿素氮(BUN)和血清肌酐(SCr)水平,观察肾功能变化；HE、Masson染色观察大鼠肾组织形态学改变；免疫组化、ⅤVestern blot法检测Ⅰ型胶原(Col Ⅰ)、Ⅲ型胶原(ColⅢ)、纤维连接蛋白(FN)蛋白表达水平,观察肾组织细胞外基质积聚的情况；免疫组化、Western blot.RT-PCR法检测肾组织缺氧诱导因子1α (HIF-1α).结缔组织生长因子(CTGF)、血浆纤溶酶原激活物抑制物-1(PAI-1)、金属基质蛋白酶组织抑制因子-1(TIMP-1)蛋白及mRNA的表达,观察HIF-1信号通路对肾间质纤维化的影响。
结果：
1、六味地黄汤能降低5/6肾切除12周后大鼠24h尿蛋白,能降低BUN和SCr水平,能减轻大鼠肾组织肾小球硬化、肾小管萎缩及间质纤维化程度,具有保护和修复肾脏组织的作用。
2、六味地黄汤能降低5/6肾切除12周后大鼠肾组织中ColⅠ、ColⅢ、 FN蛋白表达水平,具有改善细胞外基质积聚的作用。
3、六味地黄汤能降低5/6肾切除12周后大鼠肾组织HIF-1α、 CTGF、PAI-1、TIMP-1蛋白及：mRNA表达水平,具有下调HIF-1信号通路,延缓肾间质纤维化的作用。
结论：六味地黄汤能改善晚期肾间质纤维化大鼠肾功能、减轻肾脏组织形态变化及减少细胞外基质的积聚,其作用机制可能通过抑制HIF-1信号通路,因而明确了其抗肾间质纤维化的作用机制,同时HIF-1α可作为抗肾间质纤维化治疗的新靶点。
Objective:To observe the effect of Liuweidihuang Decoction on renal interstitial fibrosis in rats with5/6nephrectomy, and to explore its mechanism from the HIF-1signal pathway.
Methods:Eighty healthy male Sprapue-Demey rats were randomly divided into blank control group, sham operation group, model group, Liuweidihuang Decoction group and enalapril group. The method of5/6nephrectomy was used to construct animal model of renal interstitial fibrosis. Rats were killed after12weeks, urine and abdominal aortic blood were collected to test24h urine protein, BUN and SCr respectively, which to monitor the changes of renal function. HE and Masson staining methods were used to observe the morphological changes of the renal tissues in rats. Immunohistochemistry and Western blot method were used to detect expression level of Col I, Col III and FN protein, which to observe the deposition of extracellular matrix. Immunohistochemistry, Western blot and RT-PCR methods were used to detection of expression levels of HIF-1a, CTGF, PAI-1and TIMP-1, which to observe the effect of HIF-1signal pathway on renal interstitial fibrosis.
Result:
1. Liuweidihuang Decoction can reduce24h urine protein, BUN and SCr levels in rats with5/6nephrectomy after12weeks. It also can attenuate the renal tissue of rats with glomerulosclerosis, tubular atrophy and interstitial fibrosis. Liuweidihuang Decoction has the function of protect and restore kidney.
2. After12weeks, Liuweidihuang Decoction decrease expression levels of Col I, Col Ⅲand FN protein in rats renal tissue with5/6nephrectomy, and it also can inhibit the deposition of extracellular matrix.
3. Liuweidihuang Decoction can reduce the expression protein and mRNA levels of HIF-1α, CTGF, PAI-1, TIMP-1in rats renal tissue with5/6nephrectomy after12weeks. It has the role for down-regulating HIF-1signaling pathway and delaying the interstitial fibrosis of renal.
Conclusion:Liuweidihuang Decoction can improve renal interstitial fibrosis of kidney function, relieve pathological advancement of renal tissue and inhibit the extracellular matrix accumulation, and its mechanism of renal interstitial fibrosis may be correlated with down-regulation of HIF-1signaling pathway. Our results suggest HIF-1α can be used as a new target of renal interstitial fibrosis therapy.
引文
[1]沙朝晖,付平,周莉,等.大鼠5/6肾切除慢性肾功能衰竭动物模型的实验研究[J].四川动物,2006,25(3)：632-634.
[2]Tanaka T, Nakanishi T, Hasuike Y, et al. Paradoxical effect of L-arginine on nitric oxide (NO) synthesis and histopathological changes in 5/6 nephrectomized SD rats[J].Nihon Jinzo Gakkai Shi,1999,41 (8):754-763.
[3]Hodgkins KS, Schnaper HW. Tubulointerstitial injury and the progression of chronic kidney disease[J]. Pediatr Nephrol,2012,27(6):901-909.
[4]王琳娜,宁旺斌,陶立坚,等.动态观察依那普利对单侧输尿管梗阻大鼠TGF-1, CTGF, Smad7和α-SMA的影响[J].中南大学学报(医学版),2009,34 (3):252-258.
[5]Fu W, Wang Y, Jin Z, et al. Losartan alleviates renal fibrosis by down-regulating HIF-la and up-regulating MMP-9/TIMP-1 in rats with 5/6 nephrectomy[J]. Ren Fail,2012,34 (10):1297-1304.
[6]Abe T, Isaka Y, Imamura R, et al. Carbamylated erythropoietin ameliorates cyclosporine nephropathy without stimulating erythropoiesis[J]. Cell Transplant. 2012,21 (2-3):571-580.
[7]Wei MG, Sun W, Xiong PH, et al. Antifibrotic effect of the Chinese herbs Modified Danggui Buxue Decoction on adriamycin-induced nephropathy in rats[J].Chin J Integr Med,2012,18(8):591-598.
[8]Hamasaki Y, Doi K, Okamoto K, et al.3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin ameliorates renal fibrosis through HOXA13-USAG-1 pathway[J]. Lab Invest,2012,92(8):1161-1170.
[9]Fragiadaki M, Witherden AS, Kaneko T, et al. Interstitial fibrosis is associated with increased COL1A2 transcription in AA-injured renal tubular epithelial cells in vivo[J]. Matrix Biol,2011,30(7-8):396-403.
[10]Hocher B, Zart R, Schwarz A, et al. Renal endothelin system in polycystic kidney disease[J]. J Am Soc Nephrol,1998,9(7):1169-1177.
[11]Li Y, Zhou L, Liu F, et al. Mast Cell Infiltration Is Involved in Renal Interstitial Fibrosis in a Rat Model of Protein-Overload Nephropathy[J]. Kidney Blood Press Res,2010,33 (3):240-248.
[12]Oliveira FA, Moraes AC, Paiva AP, et al. Low-level laser therapy decreases renal interstitial fibrosis[J]. Photomed Laser Surg,2012,30(12):705-713.
[13]Wang HJ, Varner A, AbouShwareb T, et al. Ischemia/reperfusion-induced renal failure in rats as a model for evaluating cell therapies[J]. Ren Fail,2012,34(10): 1324-1332.
[14]余荣杰,赵洪雯,李敛,等.海带多糖对大鼠阿霉素肾病的抗炎症性损伤治疗作用[J].重庆医学,2008,37(8)：800-802,898.
[15]Bledsoe G, Shen B, Yao YY, et al. Role of tissue kallikrein in prevention and recovery of gentamicin-induced renal injury [J]. oxicol Sci,2008,102 (2): 433-443.
[16]Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease:the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease[J]. N Engl J Med,1982,307 (11): 652-659.
[17]金惠铭,王建枝.病理生理学[M].北京：人民卫生出版社,2008：259.
[18]Basile DP, Zeng P, Friedrich JL, et al. Low proliferative potential and impaired angiogenesis of cultured rat kidney endothelial cells[J]. Microcirculation,2012, 19 (7):598-609.
[19]李冀.方剂学[M].北京：中国中医药出版社,2006：65.
[20]许杰红,庞伟.六味地黄丸治疗慢性肾衰对内皮素、白介素-8及肌酐影响的临床研究[J].新中医,2004,36(7)：11-12
[21]吕妍,王新,唐方.六味地黄制剂对糖尿病肾病大鼠肾功能的影响[J].中草药,2005,36(9)：1379-1380,1411
[22]何剑成,董滟,董慧君.六味地黄丸对早期糖尿病肾病合并高同型半胱氨酸血症患者肾功能影响的临床研究[J].时珍国医国药,2009,20(2)：380-381.
[23]邓红,王新,徐芳,等.六味地黄汤对糖尿病肾病大鼠肾功能及细胞凋亡的影响[J].中草药,2010,(10)：1679-1682.
[24]何泽云,徐元美.六味地黄汤治疗肾阴虚型慢性肾小球肾炎的临床研究.湖南中医学院学报[J].2004,24(1)：35-37.
[25]何泽云,阳晓.参麦注射液对5/6肾切除大鼠肾脏及腹膜形态结构的影响[J].中国中西医结合杂志,1998,18(9)：553-555.
[26]何泽云,陈江华,李晓峰.六味地黄汤对肾切除大鼠肾小球化生的影响[J].湖 南中医学院学报,2004,24(2)：1-3.
[27]蔡惠芳,谭元生,何泽云,等.六味地黄汤对大鼠5/6肾切除肾功能的影响[J].湖南中医药大学学报,2007,27(2)：17-19.
[28]李万斌,何泽云.六味地黄汤延缓5/6肾切除大鼠肾组织纤维化研究[J].中国药师,2009,12(4)：411-413.
[29]Tylicki L.Lizakowski S, Rutkowski B. Renin-angiotensin-aldosterone system blockade for nephroprotection:current evidence and future directions[J]. J Nephrol,2012,25 (6):900-910.
[l]Long YB, Qin YH, Zhou TB, et al. Association of retinoic Acid receptors with extracellular matrix accumulation in rats with renal interstitial fibrosis disease. Int J Mol Sci,2012,13(11):14073-1485.
[2]谢席胜,左川,张紫媛,等.引经药物介导三七抗肾间质纤维化及肾靶向作用研究[J].四川大学学报：医学版,2012,43(1)：28-33.
[3]俞东容.中药抗肾间质纤维化机制研究[J].浙江中医药大学学报,2006,30(6)：694-695.
[4]Li JH, Zhu HJ, Huang XR, et al. Smad7 inhibits fibrotic effect of TGF-Beta on renal tubular epithelial cells by blocking Smad2 activation[J]. J Am Soc Nephrol, 2002,13 (6):1464-72.
[5]孟瑶,李建民,任文英.通络保肾复方对5/6肾切除大鼠模型Ⅰ型胶原蛋白和VEGF的影响[J].北京中医药,2008,27(11)885-887.
[6]张春,朱忠华,刘建社,等.结缔组织生长因子在单侧输尿管梗阻大鼠肾脏中的表达及其意义[J].中国病理生理杂志,2007,23(9)：1786-1790.
[7]李均,曹轶璇,王冬,等.黄芪-丹参药对及其组分对肾纤维化梗阻大鼠肾组织Ⅰ、Ⅲ型胶原的影响[J].辽宁中医杂志,2012,39(8)：1640-1642.
[8]杨桂染,刘娜,杨艳梅.顺铂致肾损伤大鼠Ⅲ型胶原表达的变化[J].现代中西医结合杂志,2010,19(36)：4671-4672.
[9]张亮,刘玉强,李远,等.梗阻性肾病肾纤维化与血清中Ⅲ型胶原变化的相关性研究[J].山东大学学报：医学版,2009,47(12)：29-32.
[10]谢议凤,王全胜,刘建国,等.血竭素高氯酸盐抑制高糖诱导的人肾小球系膜细胞中SGK1和FN的表达[J].中国中药杂志,2010,(15)：1996-2000.
[11]易继飞,王全胜,张丽晓,等.血竭素高氯酸盐抑制高糖/SGK 1/FN通路防治糖尿病肾病小鼠肾纤维化[J].华中科技大学学报：医学版,2010,39(1)：69-72,86.
[12]孟瑶,李建民,任文英,等.通络保肾复方对5/6肾切除后6周大鼠肾功能及肾组织FN表达的影响[J].中国中医基础医学杂志,2007,13(8)：583-584.
[13]吉勤,李潇,谢江海,等.降浊颗粒对慢性肾衰竭大鼠肾组织纤维连接蛋白的影响[J].中国医药导报,2012,9(28)：18-20.
[14]张竹君,赵健雄,李建华.蛭倍煎治疗肾间质纤维化的实验研究[J].四川中医,2005,23(5)：25-26.
[15]程红新,杨晓萍,蒋雅红,等.纤维连接蛋白在肾间质纤维化大鼠肾组织中的表达[J].中国组织工程研究,2012,16(31)：5837-5842.
[1]金惠铭,王建枝.病理生理学[M].北京：人民卫生出版社,2008：259.
[2]Razzaque MS, Taguchi T. Cellular and molecular events leading to renal tubulointerstitial fibrosis[J]. Med Electron Microsc,2002,35(2):68-80.
[3]Lasky JA, Ortiz LA, Tonthat B, et al. Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis[J]. Am J Physiol, 1998,275 (2 Pt 1):L365-371.
[4]谢汝佳,孙笛,张晓林,等.糖尿病大鼠肾脏PAI-1、TIMP-1表达的变化[J].2008,33(4)：366-370.
[5]Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease:the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease[J]. N Engl J Med,1982,307(11):652-659.
[6]Yigiter M, Yildiz A, Polat B, et al.The protective effects of metyrosine, lacidipine, clonidine, and moxonidine on kidney damage induced by unilateral ureteral obstruction in rats[J]. Surg Today,2012,42(11):1051-1060.
[7]Bonventre JV. Can we target tubular damage to prevent renal function decline in diabetes[J]?Semin Nephrol,2012,32(5):452-62.
[8]Nangaku M.Hypoxia and tubulointerstitial injury:a final common pathway to end-stage renal failure[J]. Nephron Exp Nephrol,2004,98 (1):e8-12.
[9]Tanaka T, Nangaku M. Pathogenesis of tubular interstitial nephritis[J].Contrib Nephrol,2011,169:297-310.
[10]Basile DP, Zeng P, Friedrich JL, et al. Low proliferative potential and impaired angiogenesis of cultured rat kidney endothelial cells[J]. Microcirculation,2012, 19 (7):598-609.
[11]Manotham K, Tanaka T, Matsumoto M, et al. Evidence of tubular hypoxia in the early phase in the remnant kidney model [J]. J Am Soc Nephrol,2004,15 (5): 1277-1288.
[12]Zhang B, Liang X, Shi W, et al.Role of impaired peritubular capillary and hypoxia in progressive interstitial fibrosis after 56 subtotal nephrectomy of rats[J]. Nephrology(Carlton),2005,10 (4):351-357.
[13]Zeng R, Yao Y, Han M, et al. Biliverdin reductase mediates hypoxia-induced EMT via PI3-kinase and Akt[J]. J Am Soc Nephrol,2008,19 (2):380-387.
[14]俞小芳,丁小强,朱加明,等.5/6肾切除大鼠低氧诱导因子1α和2α在肾内 的表达和定位[J].中华肾脏病杂志,2010,(9)：689-695.
[15]Ma YY, Sun D, Li J, et al.Transplantation of endothelial progenitor cells alleviates renal interstitial fibrosis in a mouse model of unilateral ureteral obstruction[J]. Life Sci,2010,86(21-22):798-807.
[16]Norregaard R, Bodker T, Jensen BL, et al.Increased renal adrenomedullin expression in rats with ureteral obstruction[J]. Am J Physiol Regul Integr Comp Physiol,2009,296 (1):R185-92.
[17]Kairaitis LK, Wang Y, Gassmann M, et al. HIF-lalpha expression follows micro vascular loss in advanced murine adriamycin nephrosis[J]. Am J Physiol Renal Physiol,2005,288(1):F198-206.
[18]Fine LG, Norman JT. Chronic hypoxia as a mechanism of progression of chronic kidney diseases:from hypothesis to novel therapeutics [J]. Kidney Int,2008,74 (7):867-872.
[19]Manotham K, Tanaka T, Matsumoto M, et al.Transdifferentiation of cultured tubular cells induced by hypoxia[J]. Kidney Int,2004,65(3):871-80.
[20]Chiang CK, Tanaka T, Nangaku M.Dysregulated oxygen metabolism of the kidney by uremic toxins:review[J]. J Ren Nutr,2012,22(1):77-80.
[21]Takiyama Y, Harumi T, Watanabe J, et al. Tubular injury in a rat model of type 2 diabetes is prevented by metformin:a possible role of HIF-lα expression and oxygen metabolism [J]. Diabetes,2011,60(3):981-992.
[22]Higgins DF, Kimura K, Iwano M, et al. Hypoxia-inducible factor signaling in the development of tissue fibrosis[J]. Cell Cycle,2008,7(9):1128-1132.
[23]Copple BL, Bai S, Burgoon LD, et al. Hypoxia-inducible factor-lα regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis[J]. Liver Int,2011,31 (2):230-244.
[24]Song YR, You SJ, Lee YM, et al. Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney[J].Nephrol Dial Transplant,2010, 25 (1):77-85.
[25]Kimura K, Iwano M, Higgins DF, et al. Stable expression of HIF-1 alpha in tubular epithelial cells promotes interstitial fibrosis [J].Am J Physiol Renal Physiol,2008,295 (4):F1023-1029.
[26]Haase VH. Pathophysiological Consequences of HIF Activation:HIF as a modulator of fibrosis[J]. Ann NY Acad Sci,2009,1177:57-65.
[27]张春,朱忠华,刘建社,等.结缔组织生长因子在单侧输尿管梗阻大鼠肾脏中 的表达及其意义[J].中国病理生理杂志,2007,23(9)：1786-1790.
[28]高绪霞,黄海长,李晓玫.雷帕霉素抑制结缔组织生长因子诱导的成肌纤维细胞增殖及细胞外基质蛋白的分泌[J].中华肾脏病杂志,2009,(9)：678-682.
[29]Tong M, Wang Y, Wang Y, et al. Genistein attenuates advanced glycation end product-induced expression of fibronectin and connective tissue growth factor[J]. Am J Nephrol,2012,36(1):34-40.
[30]Rosin NL, Falkenham A, Sopel MJ, et al. Regulation and role of connective tissue growth factor in Angll-induced myocardial fibrosis[J]. Am J Pathol,2012,182 (3):714-726.
[31]Sakai N, Chun J, Duffield JS, et al. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation[J]. FASEB J, 2013,190 (3):1239-1249.
[32]Lipson KE, Wong C, Teng Y, et al. CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis[J]. Fibrogenesis Tissue Repair,2012,5 (Suppl 1):S24.
[33]Jiang YF, Sun HL, Zhang JJ, et al. Effect of shRNA-mediated silencing of CTGF and TIMP-1 on mRNA expression of CTGF, TIMP-1, and PC I and secretion of extracellular matrix in rat hepatic stellate cells[J]. Zhonghua Gan Zang Bing Za Zhi,2012,20 (8):576-580.
[34]陈继贵,邰智慧,刘坤,等.肾间质纤维化中结缔组织生长因子(CTGF)与肾小管上皮细胞表型转化的关系[J].中国实验诊断学,2010,(1)：69-71.
[35]Li GM, Li DG, Fan JG, et al. Effect of silencing connective tissue growth factor on the liver fibrosis in rats[J]. Zhonghua Gan Zang Bing Za Zhi,2010,18(11): 822-825.
[36]Higgins DF, Biju MP, Akai Y, et al. Hypoxic induction of Ctgf is directly mediated by Hif-1 [J]. Am J Physiol Renal Physiol 2004,287 (6):1223-1232.
[37]Xu H, Liu X, Ning W, et al. Expression of HIF-1 alpha in 5/6-nephrectomized rat models of chronic kidney fibrosis[J]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2009,34 (4):308-312.
[38]刘玉宁,陈以平,王立红,等.蝉花菌丝对单侧输尿管结扎大鼠肾间质uPA、PAI-1蛋白及mRNA表达的影响[J].中国中西医结合肾病杂志,2012,13(3)：197-200.
[39]刘艳红,韩子明.双环醇对单侧输尿管梗阻大鼠肾间质PAI-1表达的影响[J].中国当代儿科杂志,2011,13(6)：509-513.
[40]丁红,毕莹,王宗谦,等.丹参酮ⅡA磺酸钠对TGF-β1诱导肾小管上皮细胞PAI-1表达的影响[J].中国医学工程,2011,19(4)：35-37.
[41]Malgorzewicz S, Skrzypczak-Jankun E, Jankun J. Plasminogen activator inhibitor-1 in kidney pathology (Review)[J]. Int J Mol Med,2013,31 (3): 503-510.
[42]杨红霞,宋恩峰,丁国华,等.黄芪对肾间质纤维化模型大鼠肾组织MMP-9 /TIMP-1表达的影响[J].临床肾脏病杂志,2012,12(2)：82-84.
[43]李健芝,庾江东,刘玉明.川芎嗪对肾间质纤维化大鼠中MMP-9、TIMP-1表达的影响[J].医学理论与实践,2012,25(3)：249-251.
[44]宋立群,于思明,郭丹丹,等.虫草肾茶胶囊对5/6肾切除大鼠残肾组织MMP-2与TIMP-1表达的影响[J].辽宁中医杂志,2009,36(11)：1860-1862.
[45]Ahn YT, Chua MS, Whitlock JP Jr, et al. Rodent-specific hypoxia response elements enhance PAI-1 expression through HIF-1 or HIF-2 in mouse hepatoma cells[J]. Int J Oncol,2010,37(6):1627-1638.
[46]Jung SY, Song HS, Park SY,et al. Pyruvate promotes tumor angiogenesis through HIF-1-dependent PAI-1 expression [J]. Int J Oncol,2011,38(2):571-576.
[47]Schelter F, Halbgewachs B, Baumler P, et al. Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-la[J].Clin Exp Metastasis,2011,28(2):91-99.
[48]李万斌,何泽云.六味地黄丸延缓5/6肾切除大鼠肾组织纤维化研究[J].中国药师,2009,12(4)：411-413.
[49]齐亮,何泽云,郭建.怡肾汤对肾间质纤维化大鼠TGF-β1及Ⅲ型胶原纤维表达的影响[J].上海中医药杂志,2010,(10)：76-80.
[50]彭亚平,何泽云,刘伟平.怡肾汤对腺嘌呤致肾衰竭大鼠肾间质BMP-7及a-SMA表达的影响[J].中国中西医结合肾病杂志,2011,12(5)：393-396,473.
[51]张继波,彭亚军,何泽云,等.六味地黄汤对UUO大鼠肾组织Fas和FasL表达的影响[J].中国中西医结合肾病杂志,2011,12(2)：112-116.
[1]Klein J, Miravete M, Buffin-Meyer B, et al. Tubulo-interstitial fibrosis:an emerging major health problem[J]. Med Sci (Paris),2011,27(1):55-61.
[2]Copple BL, Bai S, Burgoon LD, et al. Hypoxia-inducible factor-lα regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis[J]. Liver Int,2011,31 (2):230-244.
[3]Takiyama Y, Harumi T, Watanabe J, et al. Tubular injury in a rat model of type 2 diabetes is prevented by metformin:a possible role of HIF-la expression and oxygen metabolism[J]. Diabetes,2011,60(3):981-992.
[4]Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptionalactivation[J].Mol Cell Biol,1992,12(12):5447-5454.
[5]Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1[J].J Biol Chem,1995,270 (3):1230-1237.
[6]Wang GL, Jiang BH, Rue EA, et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular 02 tension[J]. Proc Natl Acad Sci U S A,1995,92(12):5510-5514.
[7]Jiang BH, Zheng JZ, Leung SW, et al. Transactivation and inhibitory domains of hypoxia-inducible factor lalpha. Modulation of transcriptional activity by oxygen tension[J]. J Biol Chem,1997,272(31):19253-19260.
[8]Kondo K, Kaelin WG Jr. The von Hippel-Lindau tumor suppressor gene[J]. Exp Cell Res,2001,264(1):117-125.
[9]徐钰祥,张史昭.缺氧诱导因子-1在肾脏疾病中的研究进展[J].中国中西医结合肾病杂志,2009,10(12)：1118-1121.
[10]Rosenberger C, Rosen S, Heyman SN. Current understanding of HIF in renal disease[J]. Kidney Blood Press Res,2005,28:325-340.
[11]Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases[J]. Nat Rev Mol Cell Biol,2004,5 (5):343-354.
[12]Sharp FR, Bernaudin M. HIF-1 and oxygen sensing in the brain[J].Nat Rev Neurosci,2004,5(6):437-448.
[13]Arjumand W, Sultana S. Role of VHL gene mutation in human renal cell carcinoma[J]. Tumour Biol,2012,33 (1):9-16.
[14]Wang PP, Kong FP, Chen XQ, et al. HIF-1 signal pathway in cellular response to hypoxia[J]. Zhejiang Da Xue Xue Bao Yi Xue Ban,2011,40 (5):559-566.
[15]Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism[J]. Cell Cycle,2008,7(1):28-32.
[16]Zhang Z, Yan J, Chang Y, et al. Hypoxia inducible factor-1 as a target for neurodegenerative diseases[J].Curr Med Chem,2011,18 (28):4335-4343.
[17]刘玉宁.肾间质纤维化的中医病机和治法探讨[J].新中医,2006,38(11)：1-3.
[18]郭小雷,陈敏,王怡.肾间质纤维化的中医阐述与探微[J].辽宁中医药大学学报,2010,12(4)：243-245.
[19]Razzaque MS, Taguchi T. Cellular and molecular events leading to renal tubulointerstitial fibrosis[J]. Med Electron Microsc,2002,35(2):68-80.
[20]Yang J, Liu Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal intemtitial fibrosis[J]. Am J Pathol,2001, 159 (4):1465-1475.
[21]Palm F, Nordquist L. Renal tubulointerstitial hypoxia:cause and consequence of kidney dysfunction[J]. Clin Exp Pharmacol Physiol,2011,38(7):424-430.
[22]Iwano M, Plieth D, Danoff TM, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis[J]. J Clin Invest,2002,110:341-350.
[23]于鸿,陈琦,刘哗,等.转染Smad3基因的大鼠肾系膜细胞uPA及PAI-1表达的改变[J].江苏大学学报(医学版),2008,18(3)：189-192.
[24]刘刚.NGAL在单侧输尿管梗阻大鼠肾组织中的表达[D].广州：南方医科大学,2007.
[25]Zhao W, Chen SS, Chen Y, et al. Kidney fibrosis in hypertensive rats:role of oxidative stress[J].Am J Nephrol,2008,28 (4):548-554.
[26]Ruster C, Wolf G. Angiotensin Ⅱ as a morphogenic cytokine stimulating renal fibrogenesis[J].J Am Soc Nephrol,2011,22(7):1189-1199.
[27]L6pez-Hernandez FJ, Lopez-Novoa JM. Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects[J]. Cell Tissue Res, 2012,347 (1):141-154.
[28]Hui Yao Lan. Diverse roles of TGF-β/Smads in renal fibrosis and inflammation[J]. International Journal of Biological Sciences,2011,7(7): 1056-1067.
[29]王海燕.肾脏病学[M].北京：人民卫生出版社,2008：800-801.
[30]Xu H, Liu X, Ning W, et al. Expression of HIF-1 alpha in 5/6-nephrectomized rat models of chronic kidney fibrosis[J]. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2009,34 (4):308-312.
[31]刘长林,陈永芳.结缔组织生长因子的研究进展[J].医学信息,2012,25(2)：613-614.
[32]陈继贵,邰智慧,刘坤,等.肾间质纤维化中结缔组织生长因子(CTGF)与肾小管上皮细胞表型转化的关系[J].中国实验诊断学,2010,(1)：69-71.
[33]陈莲香,舒建昌PDGF与肝纤维化关系的研究新进展[J].胃肠病学和肝病学杂志,2011,20(1)：95-98.
[34]Si HF, Lv X, Guo A, et al. Suppressive effect of leflunomide on rat hepatic stellate cell proliferation involves on PDGF-BB-elicited activation of three mitogen-activated protein kinases[J]. Cytokine,2008,42(1):24-31.
[35]Fredriksson L, Li H, Eriksson U. The PDGF family:four gene products form five dimeric isoforms[J]. Cytokine Growth Factor Rev,2004,15(4):197-204.
[36]van Roeyen CR, Ostendorf T, Floege J. The platelet-derived growth factor system in renal disease:An emerging role of endogenous inhibitors[J]. Eur J Cell Biol, 2012,91 (6-7):542-551.
[37]Tanaka T, Nangaku M. The role of hypoxia, increased oxygen consumption, and hypoxia-inducible factor-1 alpha in progression of chronic kidney disease[J]. Curr OpinNephrol Hypertens,2010,19(1):43-50.
[38]Nangaku M, Eckardt KU. Hypoxia and the HIF system in kidney disease[J]. J Mol Med(Berl),2007,85(12):1325-1330.
[39]Fine LG, Norman JT. Chronic hypoxia as a mechanism of progression of chronic kidney diseases:from hypothesis to novel therapeutics[J]. Kidney Int,2008,74 (7):867-872.
[40]Manotham K, Tanaka T, Matsumoto M, et al. Transdifferentiation of cultured tubular cells induced by hypoxia[J]. Kidney Int,2004,65(3):871-80.
[41]Chiang CK, Tanaka T, Nangaku M. Dysregulated oxygen metabolism of the kidney by uremic toxins:review[J]. J Ren Nutr,2012,22 (1):77-80.
[42]Higgins DF, Kimura K, Iwano M, et al. Hypoxia-inducible factor signaling in the development of tissue fibrosis[J]. Cell Cycle,2008,7(9):1128-1132.
[43]Song YR, You SJ, Lee YM, et al. Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney[J].Nephrol Dial Transplant,2010, 25 (1):77-85.
[44]Kimura K, Iwano M, Higgins DF, et al. Stable expression of HIF-1 alpha in tubular epithelial cells promotes interstitial fibrosis[J]. Am J Physiol Renal Physiol,2008,295(4):F1023-1029.
[45]Haase VH. Pathophysiological Consequences of HIF Activation:HIF as a modulator of fibrosis[J]. Ann N Y Acad Sci,2009,1177:57-65.
[46]Eckardt KU, Bernhardt W, Willam C, et al.Hypoxia-inducible transcription factors and their role in renal disease[J]. Semin Nephrol,2007,27 (3) 363-372.
[47]Schelter F, Halbgewachs B, Baumler P, et al. Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-la[J]. Clin Exp Metastasis,2011,28 (2):91-99.
[48]Kietzmann T, Roth U, Jungermann K. Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes [J]. Blood,1999,94 (12):4177-4185.
[49]Tang L, Yi R, Yang B, et al. Valsartan inhibited HIF-1α pathway and attenuated renal interstitial fibrosis in streptozotocin-diabetic rats[J]. Diabetes Res Clin Pract,2012,97 (1):125-131.
[50]Higgins DF, Biju MP, Akai Y, et al. Hypoxic induction of Ctgf is directly mediated by Hif-1 [J]. Am J Physiol Renal Physiol,2004,287:F1223-1232.
[51]Shin JM, Kim J, Kim HE, et al. Enhancement of differentiation efficiency of hESCs into vascular lineage cells in hypoxia via a paracrine mechanism[J].Stem Cell Res,2011,7(3):173-185.
[52]Mermis J, Gu H, Xue B, et al. Hypoxia-inducible factor-1 α/platelet derived growth factor axis in HIV-associated pulmonary vascular remodeling[J]. Respir Res,2011,12 (1):103.
[53]Ishizuka T, Hinata T, Watanabe Y. Superoxide induced by a high-glucose concentration attenuates production of angiogenic growth factors in hypoxic mouse mesenchymal stem cells[J]. J Endocrinol,2011,208(2):147-159.
[54]Mizuno S, Bogaard HJ, Kraskauskas D, et al. p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice[J]. Am J Physiol Lung Cell Mol Physiol,2011,300 (5):L753-61.
[55]Copple BL, Bustamante JJ, Welch TP, et al. Hypoxia-inducible factor-dependent production of profibrotic mediators by hypoxic hepatocytes[J]. Liver Int,2009, 29 (7):1010-1021.
[56]Copple BL, Kaska S, Wentling C. Hypoxia-inducible factor activation in myeloid cells contributes to the development of liver fibrosis in cholestatic mice[J]. J Pharmacol Exp Ther,2012,341 (2):307-316.
[57]Ueno M, Maeno T, Nomura M, et al. Hypoxia-inducible factor-la mediates TGF-β-induced PAI-1 production in alveolar macrophages in pulmonary fibrosis[J]. Am J Physiol Lung Cell Mol Physiol,2011,300 (5):L740-752.
[58]Basu RK, Hubchak S, Hayashida T, et al. Interdependence of HIF-la and TGF-β/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression[J]. Am J Physiol Renal Physiol,2011,300(4):F898-905.
[59]Kimura K, Iwano M. Molecular mechanisms of tissue fibrosis [J].Nihon Rinsho Meneki Gakkai Kaishi,2009,32(3):160-167.
[60]Du R, Sun W, Xia L, et al. Hypoxia-induced down-regulation of microRNA-34a promotes EMT by targeting the Notch signaling pathway in tubular epithelial cells[J]. PLoS One,2012,7(2):e30771.
[61]Copple BL. Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms[J]. Liver Int,2010,30(5):669-682.
[62]Zhou G, Dada LA, Wu M, et al. Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1[J]. Am J Physiol Lung Cell Mol Physiol,2009,297 (6):L1120-1130.
[63]Higgins DF, Kimura K, Bernhardt WM, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition[J]. J Clin Invest,2007,117 (12):3810-3820.
[64]Sun S, Ning X, Zhang Y, et al. Hypoxia-inducible factor-1 alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition[J]. Kidney Int,2009,75 (12):1278-1287.
[65]Sun S, Du R, Xia L, et al. Twist is a new prognostic marker for renal survival in patients with chronic kidney disease[J]. Am J Nephrol,2012,35(2):141-151.
[66]Haase VH. The sweet side of HIF[J]. Kidney Int,2010,78(1):10-13.
[67]Song YR, You SJ, Lee YM, et al. Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney[J]. Nephrol Dial Transplant,2010, 25 (1):77-85.
[2]Tanaka T, Nakanishi T, Hasuike Y, et al. Paradoxical effect of L-arginine on nitric oxide (NO) synthesis and histopathological changes in 5/6 nephrectomized SD rats[J].Nihon Jinzo Gakkai Shi,1999,41 (8):754-763.
[3]Hodgkins KS, Schnaper HW. Tubulointerstitial injury and the progression of chronic kidney disease[J]. Pediatr Nephrol,2012,27(6):901-909.
[4]王琳娜,宁旺斌,陶立坚,等.动态观察依那普利对单侧输尿管梗阻大鼠TGF-1, CTGF, Smad7和α-SMA的影响[J].中南大学学报(医学版),2009,34 (3):252-258.
[5]Fu W, Wang Y, Jin Z, et al. Losartan alleviates renal fibrosis by down-regulating HIF-la and up-regulating MMP-9/TIMP-1 in rats with 5/6 nephrectomy[J]. Ren Fail,2012,34 (10):1297-1304.
[6]Abe T, Isaka Y, Imamura R, et al. Carbamylated erythropoietin ameliorates cyclosporine nephropathy without stimulating erythropoiesis[J]. Cell Transplant. 2012,21 (2-3):571-580.
[7]Wei MG, Sun W, Xiong PH, et al. Antifibrotic effect of the Chinese herbs Modified Danggui Buxue Decoction on adriamycin-induced nephropathy in rats[J].Chin J Integr Med,2012,18(8):591-598.
[8]Hamasaki Y, Doi K, Okamoto K, et al.3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin ameliorates renal fibrosis through HOXA13-USAG-1 pathway[J]. Lab Invest,2012,92(8):1161-1170.
[9]Fragiadaki M, Witherden AS, Kaneko T, et al. Interstitial fibrosis is associated with increased COL1A2 transcription in AA-injured renal tubular epithelial cells in vivo[J]. Matrix Biol,2011,30(7-8):396-403.
[10]Hocher B, Zart R, Schwarz A, et al. Renal endothelin system in polycystic kidney disease[J]. J Am Soc Nephrol,1998,9(7):1169-1177.
[11]Li Y, Zhou L, Liu F, et al. Mast Cell Infiltration Is Involved in Renal Interstitial Fibrosis in a Rat Model of Protein-Overload Nephropathy[J]. Kidney Blood Press Res,2010,33 (3):240-248.
[12]Oliveira FA, Moraes AC, Paiva AP, et al. Low-level laser therapy decreases renal interstitial fibrosis[J]. Photomed Laser Surg,2012,30(12):705-713.
[13]Wang HJ, Varner A, AbouShwareb T, et al. Ischemia/reperfusion-induced renal failure in rats as a model for evaluating cell therapies[J]. Ren Fail,2012,34(10): 1324-1332.
[14]余荣杰,赵洪雯,李敛,等.海带多糖对大鼠阿霉素肾病的抗炎症性损伤治疗作用[J].重庆医学,2008,37(8)：800-802,898.
[15]Bledsoe G, Shen B, Yao YY, et al. Role of tissue kallikrein in prevention and recovery of gentamicin-induced renal injury [J]. oxicol Sci,2008,102 (2): 433-443.
[16]Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease:the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease[J]. N Engl J Med,1982,307 (11): 652-659.
[17]金惠铭,王建枝.病理生理学[M].北京：人民卫生出版社,2008：259.
[18]Basile DP, Zeng P, Friedrich JL, et al. Low proliferative potential and impaired angiogenesis of cultured rat kidney endothelial cells[J]. Microcirculation,2012, 19 (7):598-609.
[19]李冀.方剂学[M].北京：中国中医药出版社,2006：65.
[20]许杰红,庞伟.六味地黄丸治疗慢性肾衰对内皮素、白介素-8及肌酐影响的临床研究[J].新中医,2004,36(7)：11-12
[21]吕妍,王新,唐方.六味地黄制剂对糖尿病肾病大鼠肾功能的影响[J].中草药,2005,36(9)：1379-1380,1411
[22]何剑成,董滟,董慧君.六味地黄丸对早期糖尿病肾病合并高同型半胱氨酸血症患者肾功能影响的临床研究[J].时珍国医国药,2009,20(2)：380-381.
[23]邓红,王新,徐芳,等.六味地黄汤对糖尿病肾病大鼠肾功能及细胞凋亡的影响[J].中草药,2010,(10)：1679-1682.
[24]何泽云,徐元美.六味地黄汤治疗肾阴虚型慢性肾小球肾炎的临床研究.湖南中医学院学报[J].2004,24(1)：35-37.
[25]何泽云,阳晓.参麦注射液对5/6肾切除大鼠肾脏及腹膜形态结构的影响[J].中国中西医结合杂志,1998,18(9)：553-555.
[26]何泽云,陈江华,李晓峰.六味地黄汤对肾切除大鼠肾小球化生的影响[J].湖 南中医学院学报,2004,24(2)：1-3.
[27]蔡惠芳,谭元生,何泽云,等.六味地黄汤对大鼠5/6肾切除肾功能的影响[J].湖南中医药大学学报,2007,27(2)：17-19.
[28]李万斌,何泽云.六味地黄汤延缓5/6肾切除大鼠肾组织纤维化研究[J].中国药师,2009,12(4)：411-413.
[29]Tylicki L.Lizakowski S, Rutkowski B. Renin-angiotensin-aldosterone system blockade for nephroprotection:current evidence and future directions[J]. J Nephrol,2012,25 (6):900-910.
[l]Long YB, Qin YH, Zhou TB, et al. Association of retinoic Acid receptors with extracellular matrix accumulation in rats with renal interstitial fibrosis disease. Int J Mol Sci,2012,13(11):14073-1485.
[2]谢席胜,左川,张紫媛,等.引经药物介导三七抗肾间质纤维化及肾靶向作用研究[J].四川大学学报：医学版,2012,43(1)：28-33.
[3]俞东容.中药抗肾间质纤维化机制研究[J].浙江中医药大学学报,2006,30(6)：694-695.
[4]Li JH, Zhu HJ, Huang XR, et al. Smad7 inhibits fibrotic effect of TGF-Beta on renal tubular epithelial cells by blocking Smad2 activation[J]. J Am Soc Nephrol, 2002,13 (6):1464-72.
[5]孟瑶,李建民,任文英.通络保肾复方对5/6肾切除大鼠模型Ⅰ型胶原蛋白和VEGF的影响[J].北京中医药,2008,27(11)885-887.
[6]张春,朱忠华,刘建社,等.结缔组织生长因子在单侧输尿管梗阻大鼠肾脏中的表达及其意义[J].中国病理生理杂志,2007,23(9)：1786-1790.
[7]李均,曹轶璇,王冬,等.黄芪-丹参药对及其组分对肾纤维化梗阻大鼠肾组织Ⅰ、Ⅲ型胶原的影响[J].辽宁中医杂志,2012,39(8)：1640-1642.
[8]杨桂染,刘娜,杨艳梅.顺铂致肾损伤大鼠Ⅲ型胶原表达的变化[J].现代中西医结合杂志,2010,19(36)：4671-4672.
[9]张亮,刘玉强,李远,等.梗阻性肾病肾纤维化与血清中Ⅲ型胶原变化的相关性研究[J].山东大学学报：医学版,2009,47(12)：29-32.
[10]谢议凤,王全胜,刘建国,等.血竭素高氯酸盐抑制高糖诱导的人肾小球系膜细胞中SGK1和FN的表达[J].中国中药杂志,2010,(15)：1996-2000.
[11]易继飞,王全胜,张丽晓,等.血竭素高氯酸盐抑制高糖/SGK 1/FN通路防治糖尿病肾病小鼠肾纤维化[J].华中科技大学学报：医学版,2010,39(1)：69-72,86.
[12]孟瑶,李建民,任文英,等.通络保肾复方对5/6肾切除后6周大鼠肾功能及肾组织FN表达的影响[J].中国中医基础医学杂志,2007,13(8)：583-584.
[13]吉勤,李潇,谢江海,等.降浊颗粒对慢性肾衰竭大鼠肾组织纤维连接蛋白的影响[J].中国医药导报,2012,9(28)：18-20.
[14]张竹君,赵健雄,李建华.蛭倍煎治疗肾间质纤维化的实验研究[J].四川中医,2005,23(5)：25-26.
[15]程红新,杨晓萍,蒋雅红,等.纤维连接蛋白在肾间质纤维化大鼠肾组织中的表达[J].中国组织工程研究,2012,16(31)：5837-5842.
[1]金惠铭,王建枝.病理生理学[M].北京：人民卫生出版社,2008：259.
[2]Razzaque MS, Taguchi T. Cellular and molecular events leading to renal tubulointerstitial fibrosis[J]. Med Electron Microsc,2002,35(2):68-80.
[3]Lasky JA, Ortiz LA, Tonthat B, et al. Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis[J]. Am J Physiol, 1998,275 (2 Pt 1):L365-371.
[4]谢汝佳,孙笛,张晓林,等.糖尿病大鼠肾脏PAI-1、TIMP-1表达的变化[J].2008,33(4)：366-370.
[5]Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease:the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease[J]. N Engl J Med,1982,307(11):652-659.
[6]Yigiter M, Yildiz A, Polat B, et al.The protective effects of metyrosine, lacidipine, clonidine, and moxonidine on kidney damage induced by unilateral ureteral obstruction in rats[J]. Surg Today,2012,42(11):1051-1060.
[7]Bonventre JV. Can we target tubular damage to prevent renal function decline in diabetes[J]?Semin Nephrol,2012,32(5):452-62.
[8]Nangaku M.Hypoxia and tubulointerstitial injury:a final common pathway to end-stage renal failure[J]. Nephron Exp Nephrol,2004,98 (1):e8-12.
[9]Tanaka T, Nangaku M. Pathogenesis of tubular interstitial nephritis[J].Contrib Nephrol,2011,169:297-310.
[10]Basile DP, Zeng P, Friedrich JL, et al. Low proliferative potential and impaired angiogenesis of cultured rat kidney endothelial cells[J]. Microcirculation,2012, 19 (7):598-609.
[11]Manotham K, Tanaka T, Matsumoto M, et al. Evidence of tubular hypoxia in the early phase in the remnant kidney model [J]. J Am Soc Nephrol,2004,15 (5): 1277-1288.
[12]Zhang B, Liang X, Shi W, et al.Role of impaired peritubular capillary and hypoxia in progressive interstitial fibrosis after 56 subtotal nephrectomy of rats[J]. Nephrology(Carlton),2005,10 (4):351-357.
[13]Zeng R, Yao Y, Han M, et al. Biliverdin reductase mediates hypoxia-induced EMT via PI3-kinase and Akt[J]. J Am Soc Nephrol,2008,19 (2):380-387.
[14]俞小芳,丁小强,朱加明,等.5/6肾切除大鼠低氧诱导因子1α和2α在肾内 的表达和定位[J].中华肾脏病杂志,2010,(9)：689-695.
[15]Ma YY, Sun D, Li J, et al.Transplantation of endothelial progenitor cells alleviates renal interstitial fibrosis in a mouse model of unilateral ureteral obstruction[J]. Life Sci,2010,86(21-22):798-807.
[16]Norregaard R, Bodker T, Jensen BL, et al.Increased renal adrenomedullin expression in rats with ureteral obstruction[J]. Am J Physiol Regul Integr Comp Physiol,2009,296 (1):R185-92.
[17]Kairaitis LK, Wang Y, Gassmann M, et al. HIF-lalpha expression follows micro vascular loss in advanced murine adriamycin nephrosis[J]. Am J Physiol Renal Physiol,2005,288(1):F198-206.
[18]Fine LG, Norman JT. Chronic hypoxia as a mechanism of progression of chronic kidney diseases:from hypothesis to novel therapeutics [J]. Kidney Int,2008,74 (7):867-872.
[19]Manotham K, Tanaka T, Matsumoto M, et al.Transdifferentiation of cultured tubular cells induced by hypoxia[J]. Kidney Int,2004,65(3):871-80.
[20]Chiang CK, Tanaka T, Nangaku M.Dysregulated oxygen metabolism of the kidney by uremic toxins:review[J]. J Ren Nutr,2012,22(1):77-80.
[21]Takiyama Y, Harumi T, Watanabe J, et al. Tubular injury in a rat model of type 2 diabetes is prevented by metformin:a possible role of HIF-lα expression and oxygen metabolism [J]. Diabetes,2011,60(3):981-992.
[22]Higgins DF, Kimura K, Iwano M, et al. Hypoxia-inducible factor signaling in the development of tissue fibrosis[J]. Cell Cycle,2008,7(9):1128-1132.
[23]Copple BL, Bai S, Burgoon LD, et al. Hypoxia-inducible factor-lα regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis[J]. Liver Int,2011,31 (2):230-244.
[24]Song YR, You SJ, Lee YM, et al. Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney[J].Nephrol Dial Transplant,2010, 25 (1):77-85.
[25]Kimura K, Iwano M, Higgins DF, et al. Stable expression of HIF-1 alpha in tubular epithelial cells promotes interstitial fibrosis [J].Am J Physiol Renal Physiol,2008,295 (4):F1023-1029.
[26]Haase VH. Pathophysiological Consequences of HIF Activation:HIF as a modulator of fibrosis[J]. Ann NY Acad Sci,2009,1177:57-65.
[27]张春,朱忠华,刘建社,等.结缔组织生长因子在单侧输尿管梗阻大鼠肾脏中 的表达及其意义[J].中国病理生理杂志,2007,23(9)：1786-1790.
[28]高绪霞,黄海长,李晓玫.雷帕霉素抑制结缔组织生长因子诱导的成肌纤维细胞增殖及细胞外基质蛋白的分泌[J].中华肾脏病杂志,2009,(9)：678-682.
[29]Tong M, Wang Y, Wang Y, et al. Genistein attenuates advanced glycation end product-induced expression of fibronectin and connective tissue growth factor[J]. Am J Nephrol,2012,36(1):34-40.
[30]Rosin NL, Falkenham A, Sopel MJ, et al. Regulation and role of connective tissue growth factor in Angll-induced myocardial fibrosis[J]. Am J Pathol,2012,182 (3):714-726.
[31]Sakai N, Chun J, Duffield JS, et al. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation[J]. FASEB J, 2013,190 (3):1239-1249.
[32]Lipson KE, Wong C, Teng Y, et al. CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis[J]. Fibrogenesis Tissue Repair,2012,5 (Suppl 1):S24.
[33]Jiang YF, Sun HL, Zhang JJ, et al. Effect of shRNA-mediated silencing of CTGF and TIMP-1 on mRNA expression of CTGF, TIMP-1, and PC I and secretion of extracellular matrix in rat hepatic stellate cells[J]. Zhonghua Gan Zang Bing Za Zhi,2012,20 (8):576-580.
[34]陈继贵,邰智慧,刘坤,等.肾间质纤维化中结缔组织生长因子(CTGF)与肾小管上皮细胞表型转化的关系[J].中国实验诊断学,2010,(1)：69-71.
[35]Li GM, Li DG, Fan JG, et al. Effect of silencing connective tissue growth factor on the liver fibrosis in rats[J]. Zhonghua Gan Zang Bing Za Zhi,2010,18(11): 822-825.
[36]Higgins DF, Biju MP, Akai Y, et al. Hypoxic induction of Ctgf is directly mediated by Hif-1 [J]. Am J Physiol Renal Physiol 2004,287 (6):1223-1232.
[37]Xu H, Liu X, Ning W, et al. Expression of HIF-1 alpha in 5/6-nephrectomized rat models of chronic kidney fibrosis[J]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2009,34 (4):308-312.
[38]刘玉宁,陈以平,王立红,等.蝉花菌丝对单侧输尿管结扎大鼠肾间质uPA、PAI-1蛋白及mRNA表达的影响[J].中国中西医结合肾病杂志,2012,13(3)：197-200.
[39]刘艳红,韩子明.双环醇对单侧输尿管梗阻大鼠肾间质PAI-1表达的影响[J].中国当代儿科杂志,2011,13(6)：509-513.
[40]丁红,毕莹,王宗谦,等.丹参酮ⅡA磺酸钠对TGF-β1诱导肾小管上皮细胞PAI-1表达的影响[J].中国医学工程,2011,19(4)：35-37.
[41]Malgorzewicz S, Skrzypczak-Jankun E, Jankun J. Plasminogen activator inhibitor-1 in kidney pathology (Review)[J]. Int J Mol Med,2013,31 (3): 503-510.
[42]杨红霞,宋恩峰,丁国华,等.黄芪对肾间质纤维化模型大鼠肾组织MMP-9 /TIMP-1表达的影响[J].临床肾脏病杂志,2012,12(2)：82-84.
[43]李健芝,庾江东,刘玉明.川芎嗪对肾间质纤维化大鼠中MMP-9、TIMP-1表达的影响[J].医学理论与实践,2012,25(3)：249-251.
[44]宋立群,于思明,郭丹丹,等.虫草肾茶胶囊对5/6肾切除大鼠残肾组织MMP-2与TIMP-1表达的影响[J].辽宁中医杂志,2009,36(11)：1860-1862.
[45]Ahn YT, Chua MS, Whitlock JP Jr, et al. Rodent-specific hypoxia response elements enhance PAI-1 expression through HIF-1 or HIF-2 in mouse hepatoma cells[J]. Int J Oncol,2010,37(6):1627-1638.
[46]Jung SY, Song HS, Park SY,et al. Pyruvate promotes tumor angiogenesis through HIF-1-dependent PAI-1 expression [J]. Int J Oncol,2011,38(2):571-576.
[47]Schelter F, Halbgewachs B, Baumler P, et al. Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-la[J].Clin Exp Metastasis,2011,28(2):91-99.
[48]李万斌,何泽云.六味地黄丸延缓5/6肾切除大鼠肾组织纤维化研究[J].中国药师,2009,12(4)：411-413.
[49]齐亮,何泽云,郭建.怡肾汤对肾间质纤维化大鼠TGF-β1及Ⅲ型胶原纤维表达的影响[J].上海中医药杂志,2010,(10)：76-80.
[50]彭亚平,何泽云,刘伟平.怡肾汤对腺嘌呤致肾衰竭大鼠肾间质BMP-7及a-SMA表达的影响[J].中国中西医结合肾病杂志,2011,12(5)：393-396,473.
[51]张继波,彭亚军,何泽云,等.六味地黄汤对UUO大鼠肾组织Fas和FasL表达的影响[J].中国中西医结合肾病杂志,2011,12(2)：112-116.
[1]Klein J, Miravete M, Buffin-Meyer B, et al. Tubulo-interstitial fibrosis:an emerging major health problem[J]. Med Sci (Paris),2011,27(1):55-61.
[2]Copple BL, Bai S, Burgoon LD, et al. Hypoxia-inducible factor-lα regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis[J]. Liver Int,2011,31 (2):230-244.
[3]Takiyama Y, Harumi T, Watanabe J, et al. Tubular injury in a rat model of type 2 diabetes is prevented by metformin:a possible role of HIF-la expression and oxygen metabolism[J]. Diabetes,2011,60(3):981-992.
[4]Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptionalactivation[J].Mol Cell Biol,1992,12(12):5447-5454.
[5]Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1[J].J Biol Chem,1995,270 (3):1230-1237.
[6]Wang GL, Jiang BH, Rue EA, et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular 02 tension[J]. Proc Natl Acad Sci U S A,1995,92(12):5510-5514.
[7]Jiang BH, Zheng JZ, Leung SW, et al. Transactivation and inhibitory domains of hypoxia-inducible factor lalpha. Modulation of transcriptional activity by oxygen tension[J]. J Biol Chem,1997,272(31):19253-19260.
[8]Kondo K, Kaelin WG Jr. The von Hippel-Lindau tumor suppressor gene[J]. Exp Cell Res,2001,264(1):117-125.
[9]徐钰祥,张史昭.缺氧诱导因子-1在肾脏疾病中的研究进展[J].中国中西医结合肾病杂志,2009,10(12)：1118-1121.
[10]Rosenberger C, Rosen S, Heyman SN. Current understanding of HIF in renal disease[J]. Kidney Blood Press Res,2005,28:325-340.
[11]Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases[J]. Nat Rev Mol Cell Biol,2004,5 (5):343-354.
[12]Sharp FR, Bernaudin M. HIF-1 and oxygen sensing in the brain[J].Nat Rev Neurosci,2004,5(6):437-448.
[13]Arjumand W, Sultana S. Role of VHL gene mutation in human renal cell carcinoma[J]. Tumour Biol,2012,33 (1):9-16.
[14]Wang PP, Kong FP, Chen XQ, et al. HIF-1 signal pathway in cellular response to hypoxia[J]. Zhejiang Da Xue Xue Bao Yi Xue Ban,2011,40 (5):559-566.
[15]Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism[J]. Cell Cycle,2008,7(1):28-32.
[16]Zhang Z, Yan J, Chang Y, et al. Hypoxia inducible factor-1 as a target for neurodegenerative diseases[J].Curr Med Chem,2011,18 (28):4335-4343.
[17]刘玉宁.肾间质纤维化的中医病机和治法探讨[J].新中医,2006,38(11)：1-3.
[18]郭小雷,陈敏,王怡.肾间质纤维化的中医阐述与探微[J].辽宁中医药大学学报,2010,12(4)：243-245.
[19]Razzaque MS, Taguchi T. Cellular and molecular events leading to renal tubulointerstitial fibrosis[J]. Med Electron Microsc,2002,35(2):68-80.
[20]Yang J, Liu Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal intemtitial fibrosis[J]. Am J Pathol,2001, 159 (4):1465-1475.
[21]Palm F, Nordquist L. Renal tubulointerstitial hypoxia:cause and consequence of kidney dysfunction[J]. Clin Exp Pharmacol Physiol,2011,38(7):424-430.
[22]Iwano M, Plieth D, Danoff TM, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis[J]. J Clin Invest,2002,110:341-350.
[23]于鸿,陈琦,刘哗,等.转染Smad3基因的大鼠肾系膜细胞uPA及PAI-1表达的改变[J].江苏大学学报(医学版),2008,18(3)：189-192.
[24]刘刚.NGAL在单侧输尿管梗阻大鼠肾组织中的表达[D].广州：南方医科大学,2007.
[25]Zhao W, Chen SS, Chen Y, et al. Kidney fibrosis in hypertensive rats:role of oxidative stress[J].Am J Nephrol,2008,28 (4):548-554.
[26]Ruster C, Wolf G. Angiotensin Ⅱ as a morphogenic cytokine stimulating renal fibrogenesis[J].J Am Soc Nephrol,2011,22(7):1189-1199.
[27]L6pez-Hernandez FJ, Lopez-Novoa JM. Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects[J]. Cell Tissue Res, 2012,347 (1):141-154.
[28]Hui Yao Lan. Diverse roles of TGF-β/Smads in renal fibrosis and inflammation[J]. International Journal of Biological Sciences,2011,7(7): 1056-1067.
[29]王海燕.肾脏病学[M].北京：人民卫生出版社,2008：800-801.
[30]Xu H, Liu X, Ning W, et al. Expression of HIF-1 alpha in 5/6-nephrectomized rat models of chronic kidney fibrosis[J]. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2009,34 (4):308-312.
[31]刘长林,陈永芳.结缔组织生长因子的研究进展[J].医学信息,2012,25(2)：613-614.
[32]陈继贵,邰智慧,刘坤,等.肾间质纤维化中结缔组织生长因子(CTGF)与肾小管上皮细胞表型转化的关系[J].中国实验诊断学,2010,(1)：69-71.
[33]陈莲香,舒建昌PDGF与肝纤维化关系的研究新进展[J].胃肠病学和肝病学杂志,2011,20(1)：95-98.
[34]Si HF, Lv X, Guo A, et al. Suppressive effect of leflunomide on rat hepatic stellate cell proliferation involves on PDGF-BB-elicited activation of three mitogen-activated protein kinases[J]. Cytokine,2008,42(1):24-31.
[35]Fredriksson L, Li H, Eriksson U. The PDGF family:four gene products form five dimeric isoforms[J]. Cytokine Growth Factor Rev,2004,15(4):197-204.
[36]van Roeyen CR, Ostendorf T, Floege J. The platelet-derived growth factor system in renal disease:An emerging role of endogenous inhibitors[J]. Eur J Cell Biol, 2012,91 (6-7):542-551.
[37]Tanaka T, Nangaku M. The role of hypoxia, increased oxygen consumption, and hypoxia-inducible factor-1 alpha in progression of chronic kidney disease[J]. Curr OpinNephrol Hypertens,2010,19(1):43-50.
[38]Nangaku M, Eckardt KU. Hypoxia and the HIF system in kidney disease[J]. J Mol Med(Berl),2007,85(12):1325-1330.
[39]Fine LG, Norman JT. Chronic hypoxia as a mechanism of progression of chronic kidney diseases:from hypothesis to novel therapeutics[J]. Kidney Int,2008,74 (7):867-872.
[40]Manotham K, Tanaka T, Matsumoto M, et al. Transdifferentiation of cultured tubular cells induced by hypoxia[J]. Kidney Int,2004,65(3):871-80.
[41]Chiang CK, Tanaka T, Nangaku M. Dysregulated oxygen metabolism of the kidney by uremic toxins:review[J]. J Ren Nutr,2012,22 (1):77-80.
[42]Higgins DF, Kimura K, Iwano M, et al. Hypoxia-inducible factor signaling in the development of tissue fibrosis[J]. Cell Cycle,2008,7(9):1128-1132.
[43]Song YR, You SJ, Lee YM, et al. Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney[J].Nephrol Dial Transplant,2010, 25 (1):77-85.
[44]Kimura K, Iwano M, Higgins DF, et al. Stable expression of HIF-1 alpha in tubular epithelial cells promotes interstitial fibrosis[J]. Am J Physiol Renal Physiol,2008,295(4):F1023-1029.
[45]Haase VH. Pathophysiological Consequences of HIF Activation:HIF as a modulator of fibrosis[J]. Ann N Y Acad Sci,2009,1177:57-65.
[46]Eckardt KU, Bernhardt W, Willam C, et al.Hypoxia-inducible transcription factors and their role in renal disease[J]. Semin Nephrol,2007,27 (3) 363-372.
[47]Schelter F, Halbgewachs B, Baumler P, et al. Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-la[J]. Clin Exp Metastasis,2011,28 (2):91-99.
[48]Kietzmann T, Roth U, Jungermann K. Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes [J]. Blood,1999,94 (12):4177-4185.
[49]Tang L, Yi R, Yang B, et al. Valsartan inhibited HIF-1α pathway and attenuated renal interstitial fibrosis in streptozotocin-diabetic rats[J]. Diabetes Res Clin Pract,2012,97 (1):125-131.
[50]Higgins DF, Biju MP, Akai Y, et al. Hypoxic induction of Ctgf is directly mediated by Hif-1 [J]. Am J Physiol Renal Physiol,2004,287:F1223-1232.
[51]Shin JM, Kim J, Kim HE, et al. Enhancement of differentiation efficiency of hESCs into vascular lineage cells in hypoxia via a paracrine mechanism[J].Stem Cell Res,2011,7(3):173-185.
[52]Mermis J, Gu H, Xue B, et al. Hypoxia-inducible factor-1 α/platelet derived growth factor axis in HIV-associated pulmonary vascular remodeling[J]. Respir Res,2011,12 (1):103.
[53]Ishizuka T, Hinata T, Watanabe Y. Superoxide induced by a high-glucose concentration attenuates production of angiogenic growth factors in hypoxic mouse mesenchymal stem cells[J]. J Endocrinol,2011,208(2):147-159.
[54]Mizuno S, Bogaard HJ, Kraskauskas D, et al. p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice[J]. Am J Physiol Lung Cell Mol Physiol,2011,300 (5):L753-61.
[55]Copple BL, Bustamante JJ, Welch TP, et al. Hypoxia-inducible factor-dependent production of profibrotic mediators by hypoxic hepatocytes[J]. Liver Int,2009, 29 (7):1010-1021.
[56]Copple BL, Kaska S, Wentling C. Hypoxia-inducible factor activation in myeloid cells contributes to the development of liver fibrosis in cholestatic mice[J]. J Pharmacol Exp Ther,2012,341 (2):307-316.
[57]Ueno M, Maeno T, Nomura M, et al. Hypoxia-inducible factor-la mediates TGF-β-induced PAI-1 production in alveolar macrophages in pulmonary fibrosis[J]. Am J Physiol Lung Cell Mol Physiol,2011,300 (5):L740-752.
[58]Basu RK, Hubchak S, Hayashida T, et al. Interdependence of HIF-la and TGF-β/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression[J]. Am J Physiol Renal Physiol,2011,300(4):F898-905.
[59]Kimura K, Iwano M. Molecular mechanisms of tissue fibrosis [J].Nihon Rinsho Meneki Gakkai Kaishi,2009,32(3):160-167.
[60]Du R, Sun W, Xia L, et al. Hypoxia-induced down-regulation of microRNA-34a promotes EMT by targeting the Notch signaling pathway in tubular epithelial cells[J]. PLoS One,2012,7(2):e30771.
[61]Copple BL. Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms[J]. Liver Int,2010,30(5):669-682.
[62]Zhou G, Dada LA, Wu M, et al. Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1[J]. Am J Physiol Lung Cell Mol Physiol,2009,297 (6):L1120-1130.
[63]Higgins DF, Kimura K, Bernhardt WM, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition[J]. J Clin Invest,2007,117 (12):3810-3820.
[64]Sun S, Ning X, Zhang Y, et al. Hypoxia-inducible factor-1 alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition[J]. Kidney Int,2009,75 (12):1278-1287.
[65]Sun S, Du R, Xia L, et al. Twist is a new prognostic marker for renal survival in patients with chronic kidney disease[J]. Am J Nephrol,2012,35(2):141-151.
[66]Haase VH. The sweet side of HIF[J]. Kidney Int,2010,78(1):10-13.
[67]Song YR, You SJ, Lee YM, et al. Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney[J]. Nephrol Dial Transplant,2010, 25 (1):77-85.