摘要
随着慢性肾脏疾病(CKD)发病率的逐年上升,ESRD的发生率上升成必然趋势。导致CKD发生原因可以多种多样,但进展至ESRD的共同途径是肾脏纤维化。近几年来有关肾脏纤维化的发病机理及防治进展研究很多,虽然对已认识到的高血压,糖尿病,蛋白尿等危险因素制定了相应的治疗指南,但依然不能阻止的CKD上升趋势,说明许多研究还未能应用于临床,目前尚缺乏对CKD有效的防治措施。
目的:
1.探讨氟伐他汀对血管紧张素II诱导的肾小管上皮细胞增殖作用及其分泌纤维连接蛋白的影响。
2.研究氟伐他汀对糖尿病肾病小鼠保护作用。
3.探讨Rho激酶信号通路在糖尿病肾病间质纤维化中的作用及氟伐他汀保护机制
4.探讨氟伐他汀对高糖环境下HK2 klotho蛋白表达及细胞增殖与凋亡的影响及作用机制
方法:
1①不同浓度(10~(-9)-10~(-5) mol/L) AngII刺激体外培养的肾小管上皮细胞。②固定浓度AngII(10-6mol/L)刺激,不同浓度(10~(-9)-10~(-5) mol/L)氟伐他汀干预。③在不同的时间点(24h、48h、72h)用苯唑氮蓝法(MTT)检测细胞增殖。④固定浓度AngII(10~(-6)mol/L)刺激肾小管上皮细胞6、12、24、48、72、96小时,不同浓度(10_(-9)-10~(-5) mol/L)氟伐他汀干预48h,免疫印迹及细胞免疫荧光法检测纤维连接蛋白(FN)的表达。
2建立糖尿病小鼠模型,观察不同剂量氟伐他汀对肾重/体重比值、肾功能、蛋白尿、IL-6、FN、平滑肌肌动蛋白(α-SMA)、足细胞相关蛋白WT-1作用及影响。研究方法有生物化学法检查血尿素氮、肌酐、血糖、胆固醇、甘油三酯等,ELISA法检测尿白蛋白/肌酐比、IL-6,Western blot检测FN、α-SMA、WT-1,肾脏病理(光镜、免疫组化)观察肾脏病理改变及FN、α-SMA在肾组织分布及量的改变。
3①体外培养HK-2细胞,高糖刺激不同时间(6h、12h、24h),western blot检测p-MYPT1(磷酸化的Rho激酶)、FN表达。②.选择高糖12h作用点,观察不同剂量氟伐他汀干预后HK-2细胞p-MYPT1、FN表达。③.高糖培养HK2细胞12h,分别观察Rho激酶激动剂LPA、甲羟戊酸及其下游异戊二烯类化合物GGPP、FPP对中剂量氟伐他汀上述作用的影响。
4体外培养HK-2,观察高糖及不同浓度氟伐他汀、不同作用时间点对HK-2细胞增殖、凋亡及klotho、RhoA蛋白表达的影响,并观察分别合并MVA、FPP、GGPP对氟伐他汀作用klotho蛋白表达的影响。研究方法有苯唑氮蓝法(MTT)检测细胞增殖,Hoechst33258、检测细胞凋亡,western blot检测caspase-3、caspase-8、klotho、RhoA蛋白。
结果
1.①AngII促进肾小管上皮细胞增殖(P<0.05),48小时作用最明显,且10~(-5)mol/L效果显著,随着浓度下降,促增殖作用下降。②氟伐他汀能够显著抑制AngⅡ的促增殖作用(P<0.05),同样48小时抑制作用最明显,10~(-5)mol/L效果显著,随着浓度下降,抑制作用下降。③AngⅡ刺激肾小管上皮细胞12h后FN开始增加P<0.01),72h到达高峰。氟伐他汀干预组与AngⅡ刺激(未干预)组比较,FN表达明显下降(P<0.05),浓度10~(-5)mol/L下降最明显,10~(-6)mol/L次之,10~(-7)-10~(-9)mol/L抑制作用没有明显的差别。
2.①模型组血糖、尿白蛋白/肌酐、血尿素氮、肾重/体重比值、肾小球面积及系膜基质/肾小体面积比值,肾组织IL-6、FN、α-SMA检测均高于正常对照(P分别<0.05、0.01),WT-1低于正常对照组(P<0.05、0.01)。各剂量氟伐他汀干预1月时,尿白蛋白/肌酐、血尿素氮、肾重/体重比值、肾小球面积及系膜基质/肾小体面积比值、IL-6水平与非干预组相比有所下降,但无显著性差异(P>0.05);FN、α-SMA较非干预组下降有显著差异(P<0.01),WT-1较对照组比上升有显著性(P<0.01)。中剂量连续干预2月和3月时,尿白蛋白/肌酐、血尿素氮、肾重/体重比值、肾小球面积及系膜基质/肾小体面积比值、IL-6、FN、α-SMA水平均明显低于非干预组(P分别﹤0.05、0.01); WT-1明显高于非干预组(P<0.01)。②肾组织病理PAS显示糖尿病模型组小鼠肾小球面积和肾小体面积增大,随时间延长,系膜明显增生,细胞外基质显著增多。氟伐他汀干预后,与同期模型组小鼠相比,系膜增生及细胞外基质增多减轻。免疫组化病理显示模型组FN、α-SMA表达明显高于正常对照组,不同剂量氟伐他汀干预后FN、α-SMA表达较非干预组比均有明显下降(P<0.05、0.01)。③整个实验期间,血胆固醇及甘油三酯水平各组间均无显著差异(P>0.05)。
3.高糖刺激HK2细胞后各时间点均可引起p-MYPT1、FN表达显著增加,与0h相比(P分别<0.05),p-MYPT1表达12h最高、FN 24h达高峰,呈时间依赖(P分别<0.01)。不同剂量氟伐他汀(10~(-7), 10~(-6)和10~(-5) mol/L)干预后p-MYPT1和FN的表达均较未干预组降低,并呈浓度依赖性(P<0.05)。甲羟戊酸和GGPP可以逆转氟伐他汀的上述作用,使p-MYPT1和FN上升(P<0.05),而FPP则不能(P>0.05)。LPA激动后可部分抵消氟伐他汀的上述作用,p-MYPT1、FN表达显著高于对照组(P<0.05)。
4 HG培养HK-2至24~48h细胞增殖明显增加,与对照组比较P<0.05,而培养至72h时细胞增殖开始降低,并低于对照组P<0.05。高糖培养24~48h,细胞凋亡率及caspase3及caspase-8裂解片段增加(P分别<0.05);高糖培养12h Klotho蛋白表达减少(P<0.05)、RhoA蛋白表达增加(P<0.05),均呈时间依赖性。不同浓度氟伐他汀(0.1、1、10μmol/L)不同时间(12、24、48、72h)均明显抑制细胞增殖(P<0.05),细胞增殖抑制率具有时间-浓度依赖性。各浓度氟伐他汀(0.1、1、10μmol/L)均增加Klotho蛋白表达(P<0.05)、减少RhoA蛋白表达(P<0.05),呈浓度依赖性。减少细胞凋亡率及降低caspase-3、caspase-8的作用以浓度0.1、1、μmol/L明显(P<0.05)。氟伐他汀对HK2klotho蛋白的表达上调作用可被MVA或GGPP逆转(P<0.05),而FPP则不能(P>0.05)。
结论
1氟伐他汀能抑制AngⅡ对肾小管上皮细胞的促增殖作用及促FN分泌作用,在一定范围内呈浓度依赖性。
2氟伐他汀可以降低糖尿病小鼠蛋白尿和血尿素氮,抑制糖尿病小鼠肾脏IL-6 FN、α-SMA的表达,促进足细胞WT-1的表达,减少系膜细胞和细胞外基质的增多,改善糖尿病早期肾损害,减少肾脏纤维化,其肾保护作用独立于降血脂。
3 Rho激酶可能是糖尿病肾病间质纤维化发生的起始信号之一,他汀类药物减少糖尿病肾病间质纤维化的作用机理与其抑制Rho激酶信号通路有关。
4高糖可减少HK2 klotho蛋白表达,并同时促进细胞增殖及凋亡。他汀可部分纠正高糖对HK-2的上述作用,其机理可能与通过抑制Rho信号通路,上调HK-2 klotho蛋白有关。此结果为他汀类药物在糖尿病肾病的治疗中提供新靶点有积极作用。小结糖尿病肾病肾病发病机制复杂,炎性介质、细胞因子、各种信号通路等网络效应形成对糖尿病肾病治疗的挑战。他汀类药物独立于抗Ras、抗炎、抗氧化、抗纤维化、上调klotho的多效性作用,有望成为糖尿病肾病治疗的有力措施之一。
Over the years, the number of end stage renal diseases (ESRD) has been going up steadily due to the increased incidences of chronic kidney disease (CKD). Multiple causes can induce CKD but it is renal fibrosis that is commonly recognized as the single factor that leads to ESRD. Although there have been encouraging progress in studies regarding the mechanisms of renal fibrosis and numerous therapeutic approaches have been proposed in an attempt to control factors such as hypertension, diabetes, and proteinuria that may quicken the progression of renal disease, there seem to be no effective measures as yet in terms of preventing the development of CKD. This shows that most of the theoretical researches done so far cannot yet be applied to clinical use which really means that the prevention of CKD is still far from satisfying our expectations.
Objective:
1. To investigate the effects of Ffluvastatin on proliferation and fibronectin (FN) biosynthesis of human renal tubular epithelial cell induced by Angiotensin II.
2. To observe Fluvastatin’s influence onto expression of IL-6 in kidney,renal interstitial fibrosis,potocyte, renal function, proteinuria and to discuss statins’protective effects on renal tissues damaged by diabetes mellitus (DM).
3. To explore the effect of Rho-kinase signal pathway in renal interstitial fibrosis of diabetic nephropathy(DN) and the renopective mechanism of fluvastatin.
4. To investigate the effects and mechanism of fluvastatin on high glucose induced klotho expression, proliferation and opoptosis of human renal tubular epithelial cell(HK-2)
Method:
1①Cultured human renal tubular epithelial cells were treated with AngII at different concentrations (10~(-9)~10~(-5) mol/L respectively).②Cells were treated with 10-6 mol/L AngII and different concentrations of fluvastatin(10~(-9)~10~(-5) mol/L respectively).③The proliferation of renal tubular epithelial cells were determined by MTT colorimetry at different time(24h,.48h,72h).④Cells were treated with AngII (10~(-6) mol/L )for different time (6h, 12h, 24h, 48h, 72h, and 96h), added different concentrations of fluvastatin(10~(-9)--10~(-5)mol/L respectively)for 48h. FN expression by renal tubular cell was detected by both western blot and immunofluorescence.
2 Streptozocin(STZ)-induced diabetic model of CD-1 mice were studied. Diabitic mice were divided into three groups depend on different doses of Flufastatin treatment (5mg/kg/d,25mg/kg/d,125mg/kg/d)for 4 weeks and in dose 25mg/kg/d for 8 and 12weeks. All groups have the normal control and diabetic control. The mice were sacrificed at the end of the first, second and third month. Mouse body weight ,weight of one kidney, serum glucose(Glu), cholesterol(ch), triglyceride(TG), urea nitrogen(BUN), creatinine(Cr), and ratio of urinary albumin /creatinine (Alb/cr)were measured before and were killed. IL-6, fibronecin (FN) ,α-Smooth muscle actin (α-SMA) and WT-1 in renal tissue were detected by ELISA or Western blotting and immunohistochemistry. PAS stain was used to observe pathomorphological changes in the renal tissues.
3 Human renal proximal tubular epithelial cells(HK-2 cells) were cultured in vitro . Rho-kinase activity was expressed as phosphorylation of myosin-phosphatase target 1 (p-MYPT1). The level of p-MYPT1 and fibronectin (FN) stimulated by high glucose was determined by Western blot at the time of 6h, 12h, 24h. Same marks were detected when high glucose cultured HK-2 cells treated with different concentrations (10~(-7), 10~(-6)and 10~(-5) mol/L) of fluvastatin for 12h,and when co-treated by10-5 mol/L of fluvastatin and lysophosphatidic acid (LPA), MVA, GGPP, FPP respectively for 12h .
4 HK-2 cells were incubated with normal glucose、high glucose、fluvastatin in different concentrations for different time. HK-2 cells proliferation and apoptosis were determined by MTT and Hoechst33258 respectively. The protein expression of caspase-3, klotho and RhoA were detected by western blotting. Furthermore, the effects of fluvastatin combined with or without mevalonate (MVA), GGPP and FPP (essential molecules for isoprenylation of the small GTPase Rho) on klotho were observed.
Result:
1.①AngII can induce proliferation of human renal tubular epithelial cell(P<0.05), it was the most significantly increased for 48h, especially at the concentration of 10-5 mol/L, this effect is reduced along with the lowering concentration.②Fluvastatin can attenuate the proliferation of human renal tubular epithelial cell induced by AngII (P<0.05), that was significantly at the concentration of 10-5 mol/L for 48h.③Fibronectin synthesis by renal tubular epithelial cells cultured in AngII medium increased. The expression of FN started increasing after 12h, and achieved peak after 72h.④Fluvastatin inhibited FN expression by Ang II , the 10-5mol/L of fluvastatin had the most significant effect, and 10-6 mol/L had less effect than the 10-5mol/L, from 10-9 to 10-7mol/L, the fluvastatin had no effects on the expression of FN.
2. (1) Blood sugar level, urinary albumin/creatinine ration, urea nitrogen in blood, kidney weight/body weight ratio, IL-6 , FN,α-SMA, renal corpuscle area, ratio of mesenterium matrix versus area of renal corpuscle in mice treated with STZ were higher than those in mice without STZ (P<0.05, 0.01 respectively ), WT-1 in mice with STZ was lowered compared with those mice STZ free (P<0.05). The marks mentioned above in all groups with Fluvastatin were decreased while WT-1 was increased compared to the group without Fluvastatin 1 or 2 months later (P<0.05, 0.01 respectively) . In addition, ratio of urinary albumin /creatinine as well as the IL-6 level tapered, presenting a time-dependent nature. (2) Renal pathology by PAS-stained show that STZ mice enlarged their area of glomerulus and area of renal corpuscle, and their mesenterium as well as extracellular matrix became proliferated obviously with time elapse. The mice treated with Fluvastatin alleviated their proliferation of mesenterium and extracellular matrix compared to those with the similar model but without Fluvastatin. Immunohistochemisty show that expression of FN,α-SMA in STZ mice were increased significantly compare with normal control (P<0.01) , and in STZ mice treated with Fluvastatin were decreased significantly compare to those mice without Fluvastatin (P<0.05,0.01). (3) Serum cholesterol and triglyceride in all groups unchanged (P>0.05).
3. High glucose enhance the expression of p-MYPT1 and FN at the time of 6h, 12h, 24h compared with the time of 0h in culured HK-2cells( P<0.05 respectively). The increase of FN expression stimulated by high glucose was in time-dependent fashion and reached the peak at 24h(P<0.01).The increased level of p-MYPT1 reached the peak at 12h(P<0.01). Fluvastatin decreased high glucose-mediated level of p-MYPT1 and FN in dose-dependent manner (P<0.05). The inhibitory effect of fluvastatin on up-regulation of p-MYPT1 and FN stimulated by high glucose was reversed by MVA, GGPP respectively (P<0.05) , partially neutralized by LPA(P<0.05) but was unchanged by FPP (P>0.05).
4. High glucos increased HK-2 cells proliferation at 24~48h(<0.05) while decreased proliferation at 72h (<0.05). When after HK-2 incubated with high glucose 24~48h, the rate of apoptosis and cleaved caspase-3 increased, RhoA expression increased meanwhile klotho expression decreased at the time of 12h and in a time-dependent manner (<0.05 respectively). Fluvastatin blunted the high glucose -induced response and ameliorated the decrease in klotho expression towards high levels in a dose-dependent (<0.05 respectively). This regulatory effect on clotho was abolished by the addition of MVA and GGPP, but not FPP.
Conclusion:
1. Fluvastatin protects against AngII-induced proliferation and FN synthesis of human renal tubular epithelial cell in a dose-dependent fashion.
2. Fluvastatin is able to reduce high glucose-induced proteinuria and improve renal function, alleviate proliferation of mesangial cells and extracellular matrix. The beneficial effect of Fluvastatin might be caused by inhibiting expression of IL-6, FN,α-SMA in renal tissue and preserving WT-1 expression in podocytes against high glucose-induced injury, so it can play the role of amelioration impairment of diabetic nephropathy early and prevent renal fibrosis. The renalprotective effects of Fluvastatin are independent on its lipid-lowering function.
3. Rho-kinase may be one of the initiation signals of renal interstitial fibrosis of DN. The mechanism of decrease renal interstitial fibrosis in DN with Fluvastatin is associated with its effect of inhibiting Rho-kinase signaling pathway.
4. High glucose can reduce HK-2 clotho expression and enhance cells proliferation and apoptosis。The mechanism of statins improving these effects by high glucose is related with statins inactivating the RhoA pathway, resulting in over-expression of klotho, which may contribute to the novel target of statins towards on treatment DN .
In clousion, Challenges exist in the treatment of diabetic nephropathy due to its complicated pathologic mechanism and considerable cytokines, signal pathways and crosstalking. Statins is expected to play a potent role in the treatment of diabetic nephropathy because of its pleiotropic effects on Ras, inflammation, oxidative stress, renal fibrosis and klotho beyond lipid lowering. Key words:
引文
1 Zoja C, Abbate M, Remuzzi G. Progression of chronic kidney disease:insights from animal models. Curr Opin Nephrol Hypertens.2006, 15: 250-257.
2 Morrisey K, Evans RA, Wakefield L, et al. Translational regulation of renal proximal tubular epithelial cell transforming growth factor-b1 generation byinsulin . Am J Pathol, 2001, 159: 1905-1915.
3 Wang SN, Raimund H. Growth factor ultrafiltration in experimental diabetic nephropathy contributes to interstitial fibrosis . Am J Physiol Renal Physiol, 2000, 278: F554-F560.
4 Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006 Jan;17(1):17-25.
5 Efstratiadis G, Divani M, Katsioulis E, Vergoulas G. Renal fibrosis. Hippokratia. 2009 ,13(4):224-9.
6 Strutz F, ZeisbergM, Hemmerlein B, et al . Basic fibroblast growth factor (FGF22) expression is increased in human renal fibrogenesis and may mediated autocrine fibroblast proliferation . Kidney Int, 2000, 57 :1521-1538.
7 Goumenos DS, Tsamandas AC, Nahas AM, et al. Apoptosis and myofibroblast expression in human glomerular disease: a possible link with transforming growth factor-21. Nephron, 2002, 92,287-296.
8 Robert L. Chevalier, Michael S. Forbes and Barbara A. Thornhill. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy.Kidney Int, 2009,75:1145–1152.
9 Hironobu I. Pathogenensis of the fibrosis : role of TGFB1 and CTGF [J ] . Curr Opion Rheumat, 2002, 14 : 681-685.
10 Wolf G. Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-beta pathway. Kidney Int. 2006;70 (11):1914-9.
11 Rodrigues-Díez R, Carvajal-González G, Sánchez-López E, Rodríguez-Vita J, Rodrigues Díez R, Selgas R, Ortiz A, Egido J, Mezzano S, Ruiz-Ortega M. Pharmacological modulation of epithelial mesenchymal transition caused by angiotensin II. Role of ROCK and MAPK pathways. Pharm Res. 2008 ,25(10):2447-61.
12 Liu BC, Xia HL, Wu JN, Zhang XL, Liu DG, Gong YX. Influence of irbesartan on expression of ILK and its relationship with epithelial-mesenchymal transition in mice with unilateral ureteral obstruction. Acta Pharmacol Sin. 2007 ,28(11):1810-8.
13 Norman JT, Fine LG. Intrarenal oxygenation in chronic renal failure. Clin Exp Pharmacol Physiol. 2006,33(10):989-96.
14 Wolf G, Ziyadeh FN. Molecular mechanisms of diabetic renal hypertrophy. Kindey Int, 1999, 56: 393-405.
15 Quesney-Huneeus V, Galick HA, Siperstein MD, Erickson SK, Spencer TA, Nelson JA.The role of mevalonate in the cycle.J Biol chem.1983 10;258(1)378-385.
16 Shibata T, Tamura M, Kabashima N, Serino R, Tokunaga M, Matsumoto M, Miyamoto T, Miyazaki M, Furuno Y, Takeuchi M, Abe H, Okazaki M, Otsuji Y.Fluvastatin attenuates IGF-1-induced ERK1/2 activation and cell proliferation by mevalonic acid depletion in human mesangial cells.Life Sci. 2009 22;84(21-22):725-31.
17 lanco S, Vaquero M, Gomez-Guerrero C. Potential role of angiotensin-converting enzyme inhibitors and statins on early podocyte damage in a model of type 2 diabetes mellitus, obesity, and mild hypertension. Am J Hypertens,2005,18: 557-565.
18 Bezerra DG, Mandarin-de-Lacerda CA. Beneficial effect of simvastatin and pravastatin treatment on adverse cardiac remodeling and glomeruli loss in spontaneously hypertensive rates. Clin Sci(lond), 2005,108(4): 349-355.
19 Toblli JE,Cao G, Casas G at al. NF-kappaB and chemikine-cytokine expression in renal tubulointerstitium in experimental hyperoxaluria. Role of the renin-angiotentsin system. Urol Res 2005;33:358-367.
20 Jandeleit-Dahm K, Cao Z, Cox AJ, et al. Role of hyperlipidemia in progressive renal disease: focus on diabetic nephropathy. Kidney Int ,1999,56(Suppl 71):31-46.
21 Bae EH, Kim IJ, Park JW, Ma SK, Lee JU, Kim SW. Renoprotective effect of rosuvastatin in DOCA-salt hypertensive rats. Nephrol Dial Transplant. 2009 Nov 30. [Epub ahead of print]
22 Reisin E, Ebenezer PJ, Liao J, Lee BS, Larroque M, Hu X, Aguilar EA, Morse SA, Francis . Effect of the HMG-CoA reductase inhibitor rosuvastatin on early chronic kidney injury in obese zucker rats fed with an atherogenic diet.Am J Med Sci. 2009 ,338(4):301-9.
23 Park JK, Mervaala EM, Muller DN, Menne J, Fiebeler A, Luft FC, Haller H.Rosuvastatin protects against angiotensin II-induced renal injury in a dose-dependent fashion. J Hypertens. 2009 ,27(3):599-605.
24 Hartner A, Klanke B, Cordasic N, Amann K, Schmieder RE, Veelken R, Hilgers KF.Statin treatment reduces glomerular inflammation and podocyte damage in rat deoxycorticosterone-acetate-salt hypertension. J Hypertens. 2009 ,27 (2):376-85.
25 Naito M, Shenoy A, Aoyama I, Koopmeiners JS, Komers R, Schnaper HW, Bomsztyk K. High ambient glucose augments angiotensin II-induced proinflammatory gene mRNA expression in human mesangial cells: effects of valsartan and simvastatin. Am J Nephrol. 2009;30(2):99-111.
26 Juliane Heusinger-Ribeiro J, Fischer B,Goppelt-Struebe M. Differential of simvastatin on mesangial cells. Kidney Int 2004;66:187-195.
27陈楠,李娅,王伟铭,等.辛伐他汀对大鼠肾间质成纤维细胞的影响.肾脏病与透析肾移植杂志, 2000,10.30,9(5):411-415.
28 Gojo A, Utsunomiya K, Taniguchi K et al. The Rho-kinase inhibitor,fasudilattenuates diabetic nephropathy in streptozotocin-induced diabetic rat. Eur J Pharmacol 2007,568:242-247.
29 Sakurai N, Kuroiwa T, Ikeuchi H, Hiramatsu N, Takeuchi S, Tomioka M, Shigehara T, Maeshima A, Kaneko Y, Hiromura K, Kopp JB, Nojima Y.Fluvastatin prevents podocyte injury in a murine model of HIV-associated nephropathy. Nephrol Dial Transplant. 2009 ,24(8):2378-83.
30刘佳,王笑云,孙彬,等.氟伐他汀对肾小球硬化大鼠纤维蛋白溶解酶原激活物抑制-1和Ⅳ型胶原的影响.南京医科大学学报, 2002, 22(6):486-488.
31 Kostapanos MS, Liberopoulos EN, Elisaf MS. Statin pleiotropy against renal injury. J Cardiometab Syndr. 2009,4(1):E4-9.
32 Linda F Fried. Effects of HMG-CoA reductase inhibitors (statins) on progression of kidney disease. Kidney International (2008) 74, 571–576.
33 Narumiya H, Sasaki S, Kuwahara N, et al. HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells. Cardiovasc Res, 2004, 64(2):331-336.
34 Kuwahara N, Sasaki S, Kobara M, et al. HMG-CoA reductase inhibition improves anti-aging klotho protein expression and arteriosclerosis in rats with chronic inhibition of nitric oxide synthesis. Int J Cardiol, 2008, 123(2), 84–-90.
35 Vito M. Campese and Jeanie Park. HMG-CoA Reductase Inhibitors and Renal Function. Clin J Am Soc Nephrol 2007, 2: 1100–1103.
1. Williams MD, Nadler JL: Inflammatory mechanisms of diabetic complications. Curr Diab Rep . 2007,7 : 242–248
2. King GL. The role of inflammatory cytokines in diabetes and its complications. J Periodontol. 2008,79(8 Suppl):1527-34
3. Juan F. Navarro-González et al. The Role of Inflammatory Cytokines in Diabetic Nephropathy. J Am Soc Nephrol 2008,19: 433-442
4. Sekizuka K, Tomino Y, et al. Detection of serum IL-6 in patients with diabetic nephropathy. Nephron 1994,68 : 284–285
5. Suzuki D, Miyazaki M, et al. In situ hybridization of interleukin 6 in diabetic nephropathy. Diabetes 1995, 44 : 1233–1238
6. Nosadini R, Velussi M, Brocco E, et al.Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes 2000, 49 : 476–484
7. Dalla Vestra M, Mussap M, Gallina P, et al. Acute-phase markers of inflammation and glomerular structure in patients with type 2 diabetes. J Am Soc Nephrol 2005, 16 [Suppl 1]: S78–S82
8. Choudhary N, Ahlawat RS. Interleukin-6 and C-reactive protein in pathogenesis of diabetic nephropathy: new evidence linking inflammation, glycemic control, and microalbuminuria. Iran J Kidney Dis 2008,2(2):72-9
9. Navarro JF, Mora C, Gómez M, et al. Influence of renal involvement on peripheral blood mononuclear cell expression behaviour of tumour necrosis factor-alpha and interleukin-6 in type 2 diabetic patients.Nephrol Dial Transplant. 2008,23(3):919-26
10. Isermann B, Vinnikov IA, Madhusudhan T, et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. 2007,Nat Med13:1349–58
11. Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M. Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. Diabetes. 2007;56:2155–60
12.Nakagawa T, Sato W, Glushakova O, et al. Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J Am Soc Nephrol 2007,18:539–50
13. Li J, Qu X, Bertram JF. Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice.Am J Pathol. 2009,175(4):1380-8
14. Liu Jia, Wang Xiao-Yun, Sun Bin,et al. Effect of Fluvastatin on Collagen Type IV and Molecular Mechanism in Rats of Glomerular Sclerosis[J]. Acta Universitatis Medicinalis Nanjing. 2004,22(6):575-579
15. Frank C. Brosius III . New insights into the mechanisms of fibrosis and sclerosisin diabetic nephropathy. Rev Endocr Metab Disord 2008;9:245–254
16. Kostapanos MS, Liberopoulos EN, Elisaf MS. Statin pleiotropy against renal injury. J Cardiometab Syndr. 2009,4(1):E4-9
17. Bettina Haslinger-L?ffler.Multiple effects of HMG-CoA reductase inhibitors (statins) besides their lipid-lowering function. Kidney International. 2008, 74, 553–555
18 .Linda F. Fried. Effects of HMG-CoA reductase inhibitors (statins) on progression of kidney disease. Kidney International 2008,74, 571–576
19 .lanco S, Vaquero M, Gomez-Guerrero C. Potential role of angiotensin-converting enzyme inhibitors and statins on early podocyte damage in a model of type 2 diabetes mellitus, obesity, and mild hypertension. Am J Hypertens,2005,18: 557-565
20 .Gojo A, Utsunomiya K, Taniguchi K et al. The Rho-kinase inhibitor,fasudilattenuates diabetic nephropathy in streptozotocin-induced diabetic rat. Eur J Pharmacol 2007,568:242-247
21 .Bezerra DG, Mandarin-de-Lacerda CA. Beneficial effect of simvastatin and pravastatin treatment on adverse cardiac remodeling and glomeruli loss in spontaneously hypertensive rates. Clin Sci(lond), 2005,108(4): 349-355.
22 .Bae EH, Kim IJ, Park JW, Ma SK, Lee JU, Kim SW. Renoprotective effect of rosuvastatin in DOCA-salt hypertensive rats. Nephrol Dial Transplant. 2009 Nov 30. [Epub ahead of print]
23 . Reisin E, Ebenezer PJ, Liao J, Lee BS, Larroque M, Hu X, Aguilar EA, Morse SA, Francis . Effect of the HMG-CoA reductase inhibitor rosuvastatin on early chronic kidney injury in obese zucker rats fed with an atherogenic diet. Am J Med Sci. 2009 ,338(4):301-9
24 . Murray Epstein, Vito M.et al.Pleiotropic Effects of 3-Hydroxy-3-MethylglutarylCoenzyme A Reductase Inhibitors on Renal Function. Am J Kidney Di. 2005;45: 2–4
25 . Sakurai N, Kuroiwa T, Ikeuchi H, Hiramatsu N, Takeuchi S, Tomioka M, Shigehara T et al. Fluvastatin prevents podocyte injury in a murine model of HIV-associated nephropathy. Nephrol Dial Transplant. 2009,24(8):2378-83.
26 . Hartner A, Klanke B, Cordasic N, Amann K, Schmieder RE, Veelken R, Hilgers KF. Statin treatment reduces glomerular inflammation and podocyte damage in rat deoxycorticosterone-acetate-salt hypertension. J Hypertens. 2009,27(2):376-85.
27 .Mo′nica Rupe′rez, Raquel Rodrigues-D?′ez, Luis Miguel Blanco-Colio, Elsa. HMG-CoA Reductase Inhibitors Decrease Angiotensin II–Induced Vascular Fibrosis (Role of RhoA/ROCK and MAPK Pathways).Hypertention. 2007,50:377-383
28 .Park JK, Mervaala EM, Muller DN, Menne J, Fiebeler A, Luft FC, Haller H.Rosuvastatin protects against angiotensin II-induced renal injury in a dose-dependent fashion. J Hypertens. 2009 Mar,27(3):599-605.
29 . Naito M, Shenoy A, Aoyama I, Koopmeiners JS, Komers R, Schnaper HW, Bomsztyk K. High ambient glucose augments angiotensin II-induced proinflammatory gene mRNA expression in human mesangial cells: effects of valsartan and simvastatin. Am J Nephrol.2009,30(2):99-111.
30 .Fitzgerald JP, Chou SY, Franco I, Mooppan UM, Kim H, Saini R, Gulmi FA. Atorvastatin ameliorates tubulointerstitial fibrosis and protects renal function in chronic partial ureteral obstruction cases. J Urol. 2009,182(4 Suppl):1860-8.
31 .Shibata T, Tamura M, Kabashima N, Serino R, Tokunaga M, Matsumoto M, Miyamoto T,et al. Fluvastatin attenuates IGF-1-induced ERK1/2 activation and cell proliferation by mevalonic acid depletion in human mesangial cells.Life Sci. 2009 ;22,84(21-22):725-31.
32 . Rodrigues-Díez R, Carvajal-González G, Sánchez-López E, Rodríguez-Vita J, et al Pharmacological modulation of epithelial mesenchymal transition caused by angiotensin II. Role of ROCK and MAPK pathways. Pharm Res. 2008,25(10):2447-61.
33 . Mather A, Chen XM, McGinn S, Field MJ, Sumual S, Mangiafico S, Zhang Y, Kelly DJ, Pollock CA. High glucose induced endothelial cell growth inhibition is associated with an increase in TGFbeta1 secretion and inhibition of Ras prenylation via suppression of the mevalonate pathway. Int J Biochem Cell Biol. 2009,41(3):561-9.
34 . Yang F, Chung AC, Huang XR, Lan HY. Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and -independent Smad pathways: the role of Smad3. Hypertension. 2009,54(4):877-84.
35 .Satoru Sharyo ,Naoko Yokota-Ikeda, Miyuki Mori, Kazuyoshi Kumagai, et al. Pravastatin improves renal ischemia–reperfusion injury by inhibiting the mevalonate pathway. Kidney International 2008,74, 577–584
36 .Slijper N, Sukhotnik I, Chemodanov E, Bashenko Y, Shaoul R, Coran AG, Mogilner J.Effect of simvastatin on intestinal recovery following gut ischemia-reperfusion injury in a rat. Pediatr Surg Int. 2009,24. [Epub ahead of print]
1孙骅,陈荣华,黄文彦,等。ROCK-Ⅰ激酶在肾间质纤维化大鼠不同阶段肾组织中的激活及意义。中华肾脏志,2004,20(2):127-131.
2 Vasantha K, Lixia Z, Hui P,et al Targeting of RhoA/ROCK signaling ameliorates progression of diabetic nephropathy independent of glucose control. Diabetes,2008, 57(3):714–723.
3 Gojo A, Utsunomiya K, Taniguchi K,et al. The Rho-kinase inhibitor, fasudil,attenuates diabetic nephropathy in streptozotocin-induced diabetic rats. Eur J Pharmacol, 2007,568(1-3):242-247.
4 Ishibashi F. High glucose increases phosphocofilin via phosphorylation of LIM kinase due to Rho/Rho kinase activation in cultured pig proximal tubular epithelial cells. Diabetes Res and clinical practice , 2008 ,80(1) :24– 33.
5 Nagatoya K, Moriyama T, Kawada N, et al. Y-27632 prevents tubulointerstitial fibrosis in mouse kidney with unilateral ureteral obstruction. Kidney Int, 2002,61(5):1684-1695.
6 Patel S, Takagi KI, Suzuki J,et al. Rho GTPase activation is a key step in renal epithelial mesenchymal transdifferentiation. J Am Soc Nephrol, 2005, 16(7): 1977–1984.
7 Fujii M, Inoguchi T, Maeda Y,et al. Pitavastatin ameliorates albuminuria and renal mesangial expansion by downregulating NOX4 in db/db mice. Kidney Int, 2007,72 (4):473–480.
8 Cardinale CJ ,Washburn RS , Tadigotla VR ,et al. Termination factor Rho and its cofactors NusA and NusG silence foreign DNA in E coli. Science ,2008 ,320 (5878) :935– 938.
9 Kataoka C, Egashira K, Inoue S, et al. Important role of Rho-kinase in thepathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats. Hypertension,2002,39(2):245–250.
10 Kolavennu V, Zeng L, Peng H, et al. Targeting of RhoA/ROCK signaling ameliorates progression of diabetic nephropathy independent of glucose control. Diabetes, 2008,57(3):714-723.
11 Akiyama N ,Naruse K, Kobayashi Y,et al. High glucose - induced upregulation of Rho/Rho - kinase via platelet– derived growth factor receptor -βincreasesmigration of aortic smooth muscle cells. J Mol Cellular Cardiology , 2008 , 45 (2) : 326 -332.
12 Zeng L ,Xu H ,Chew TL ,et al. HMG CoA reductase inhibition modulates VEGF - induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation. FASEB J , 2005 ,19 (13) :1845– 1847
13 Chu G, Jia R, Yang D. Fluvastatin prevents oxidized low-density lipoprotein-induced injury of renal tubular epithelial cells by inhibiting the phosphatidylinositol 3-kinase/Akt-signaling pathway. J Nephrol, 2006,19 (3):286-95.
14 GuL, Ni Z, Qian J, Tomino Y. Pravastatin inhibits carboxymethyllysine-induced monocyte chemoattractant protein 1 expression in podocytes via prevention of signalling events. Nephron Exp Nephrol, 2007,106 (1):e1-10.
15 Lin CL, Cheng H, Tung CW, Huang WJ, et al. Simvastatin reverses high glucose-induced apoptosis of mesangial cells via modulation of Wnt signaling pathway. Am J Nephrol, 2008;28(2):290-7.
16高苹,贾汝汉。氟伐他汀对糖尿病大鼠肾组织核因子-κB活性的影响[J]。中国中西医结合肾病杂志,2009,10(1):15-17
17倪连松,郑景晨,金洁娜,等。普伐他汀对高糖培养的肾小球系膜细胞P38促分裂原活化蛋白激酶信号通路的影响。中国药理学与毒理学杂志,2009,23(5):368-374
18 Nabumiya H, Sasaki S, Kuwahara N, et al. HMG-CoA redutase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells. Cardiovasc Res, 2004, 64(2):331-336
19 Turner NA, Aley PK, Hall KT, et al. Simvastatin inhibites TNFα-induced invasion of human cardiac myofibroblasts via both MMP-9-dependent andindependent mecabanisms. J Mol Cell Cardiol, 2007,.43(2):168-176
20 Gojo A, Utsunomiya K, Taniguchi K, et al. Tho-kinase inhibitor fasudil attenuates diabetic nephropathy in streptoztocin-induced diabetic rat. Eur J Pharmacal, 2007, 568(1-3):242-247
21 Cary B. Aarons, Philip A. Cohen, Adam Gower, et al. Statins( HMG-CoA Reductase Inhibitors) Decrease Postoperative Adhesions by Increasing Peritoneal Fibrinolytic Activity.Ann Surg, 2007, 245(2): 176-184
22 Rie Hanayama, Hideo Shimizu, Hironori Nakagami, et al. Fluvastatin improves osteoporosis in fructose-fed insulin resistant model rats through blockade of the classical mevalonate pathway and antioxidant action. Int J Mol Med, 2009, 23(5): 581-588
23 Hanshi Xu, Lixia Zeng, Hui Peng, et al. HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced“inside-out”signaling to extracellular matrix by preventing RhoA activation. Am J Physiol Renal Physiol, 2006, 291(5): F995– F 1004 ?
1 Kuro-o M, Matsumura Y, Aizawa H et al. Mutation of the mouse klotho gene leads to a syndrome resembling aging. Nature,1997:390: 45–51.
2 Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P,Mc Guinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, et al. Suppression of Aging in Mice by the Hormone Klotho.Science, 2005 ,309(5742): 1829–1833.
3 Koh N, Fujimori T, Nishiguchi S et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun, 2001, 280: 1015–1020.
4 Sugiura H, Yoshida T, Mitobe M, Yoshida S, Shiohira S, Nitta K, Tsuchiya K. Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70. Nephrol Dial Transplant, 2010 ,25(1):60-8.
5 Rakugi H, Matsukawa N, Ishikawa K, et al. Anti-oxidative effect of Klotho on endothelial cells through cAMP activation. Endocrine, 2007, 31(1): 82–87.
6 Kostapanos MS, Liberopoulos EN, Elisaf MS. Stain pleiotropy against renal injury. J Cardiometab Syndr, 2009, 4(1): E4-9.
7 Kuwahara N, Sasaki S, Kobara M, et al. HMG-CoA reductase inhibition improves anti-aging klotho protein expression and arteriosclerosis in rats withchronic inhibition of nitric oxide synthesis. Int J Cardiol, 2008, 123(2): 84–90.
8 Wang N, Fan Y, Ni P, Wang F, Gao X, Xue Q, Tang LHigh glucose effect on the role of CD146 in human proximal tubular epithelial cells in vitro. J Nephrol. 2008,21(6):931-40.
9 Huang HC , Preisig PA. Gl Kinases and transforming growth factor beta signaling are associated with a grow pattern swith in diabetes induced renal growth . Kidney Int ,2000 ,58 (1) : 162-172.
10马玉香,白光辉,白雪源,李作祥,冯哲,傅博.高糖诱导人肾小管上皮细胞凋亡的机制研究.青海医学院学报,2009, 30(3):150-154
11 Praveen N. Chander,2 and Pravin C. Singhal1 Aldosterone promotes proximal tubular cell apoptosis: role of oxidative stress. Am J Physiol Renal Physiol, 2007,293: F1065–F1071.
12 Yoshisuke Haruna, Naoki Kashihara, Minoru Satoh, Naruya Tomita, Tamehachi Namikoshi, Tamaki Sasaki, Toshihiko Fujimori, Ping Xie§and Yashpal S. Kanwar. Amelioration of progressive renal injury by genetic manipulation of Klotho gene. PNAS, 2007, 104 (7 ):2331–2336.
13 Hidekazu Sugiura1, Takumi Yoshida1,2, Ken Tsuchiya1, Michihiro Mitobe1, Sayoko Nishimura1,Satsuki Shirota1, Takashi Akiba1,2 and Hiroshi Nihei. Klotho reduces apoptosis in experimental ischaemic acute renal failure.Nephrol Dial Transplant ,2005,20: 2636–2645
14 Sugiura H, Yoshida T, Mitobe M, Yoshida S, Shiohira S, Nitta K, Tsuchiya K. Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70. Nephrol Dial Transplant, 2010,25 (1):60-8.
15 Wang Y, Sun Z.Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage. Hypertension, 2009, 54(4):810-7.
16 Hiromichi Narumiyaa, Susumu Sasakia, Noriko Kuwaharaa, Hidekazu Iriea,Tetsuro Kusabaa, Hisako Kameyamaa, Keiichi Tamagakia, Tsuguru Hattaa, Kazuo Takedaa, Hiroaki Matsubara. HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells. Cardiovascular Research , 2004,64:331– 336.
17 Kuro-o M .Klotho. Pflugers Arch,2010,459(2):333-43.
18 Masaya Yamamoto, Jeremy D. Clark, Johanne V. Pastor, Prem Gurnani, Animesh Nandi,Hiroshi Kurosu, Masayoshi Miyoshi, Yasushi Ogawa, Diego H. Castrillon, Kevin P.Rosenblatt, and Makoto Kuro-o. Regulation of Oxidative Stress by the Anti-aging Hormone Klotho. J Biol Chem,2005,280(45): 38029–38034.
19 Kurosu H, Ogawa Y, Miyoshi M, et al.Regulation of Fibroblast GrowthFactor-23 Signaling by Klotho.J Biol Chem, 2006 ,281(10): 6120-6123.
20 Yamamoto M, Clark JD, Pastor JV, et al. Regulation of oxidative stress by the anti-aging hormone klotho.J Biol Chem, 2005 ,280(45): 38029-34.
21 de Oliveira RM. Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway. FEBS Lett, 2006, 580(24): 5753–5758.
22 Rakugi H, Matsukawa N, Ishikawa K, et al. Anti-oxidative effect of Klotho on endothelial cells through cAMP activation. Endocrine, 2007, 31(1): 82–87.
23 Imai M, Ishikawa K, Matsukawa N, et al. Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression. Endocrine, 2004, 25(3): 229–234.
1 Ricci C, Iacobini C, Oddi G, et al . Role of TGF-beta/GLUT1 axis in susceptibility vs resistance to diabetic glomerulopathy in the Milan rat model . Nephrol Dial Transplant , 2006, 21: 1514-1524.
2 Mauer SM, Steffes MW, Ellis EN, et al . Structural-functional relationships in diabetic nephropathy. J Clin Invest , 1984, 74: 1143–1155.
3 Yuan WJ, Jia FY, Meng JZ. Effects of genistein on secretion of extracellular matrix components and transforming growth factor beta in high-glucose-cultured rat mesangial cells. J Artif Organs , 2009; 12: 242–246.
4 Van Huyen JP, Viltard M, Nehiri T, et al . Expression of matrix metalloproteinases MMP-2 and MMP-9 is altered during nephrogenesis in fetuses from diabetic rats. Laboratory Investigation , 2007; 87(7): 680–689.
5 Kosugi T, Heinig M, Nakayama T, et al . eNOS knockout mice with advanced diabetic nephropathy have less benefit from renin-angiotensin blockade than from aldosterone receptor antagonists. Am J Pathol , 2010; 176(2): 619-629.
6 Ristola M, Arpiainen S, Saleem MA, et a1 . Regulation of Neph3 gene in podocytes--key roles of transcription factors NF-kappaB and Sp1. BMC Mol Biol , 2009 ; 10: 83.
7 Pezzolesi MG ,Poznik GD, Mychaleckyj JC, et al . Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes , 2009; 58(6): 1403-1410.
8 Niewczas MA, Ficociello LH, Johnson AC, et al . Serum concentrations of markers of TNFalpha and Fas-mediated pathways and renal function in nonproteinuric patients with type 1 diabetes. Clin J Am Soc Nephrol , 2009; n 4(1): 62-70.
9 Tarabra E , Giunti S, Barutta F, et al . Effect of the monocyte chemoattractantprotein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes. Diabetes , 2009; 58(9): 2109-2118.
10 Usui HK, Shikata K, Sasaki M, et al . Macrophage scavenger receptor-a-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation. Diabetes , 2007; 56(2): 363-372.
11 Ogawa S, Kobori H, Ohashi N, et al . Angiotensin II Type 1 Receptor Blockers Reduce Urinary Angiotensinogen Excretion and the Levels of Urinary Markers of Oxidative Stress and Inflammation in Patients with Type 2 Diabetic Nephropathy. Biomark Insights , 2009; 4: 97-102.
12 Huang W, Gallois Y, Bouby N, et al . Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse. Proc Natl Acad Sci U S A , 2001; 98(23): 13330–13334.
13 Tan Y, Keum JS, Wang B, et al . Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy. Am J Physiol Renal Physiol , 2007; 293(4): F1026-1035.
14 Buléon M, Allard J, Jaafar A, et al . Pharmacological blockade of B2-kinin receptor reduces renal protective effect of angiotensin-converting enzyme inhibition in db/db mice model . Am J Physiol Renal Physiol , 2008; 294(5): F1249-1256.
15 Allard J, Buleon M, Cellier E, et al . ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats. Am J Physiol Renal Physiol , 2007; 293(4): F1083–F1092.
16 Thallas-Bonke V, Thorpe SR, Coughlan MT, et al . Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabeticnephropathy through a protein kinase C-alpha-dependent pathway. Diabetes , 2008; 57(2): 460–469.
17 Gorin Y, Block K, Hernandez J, et al . Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J Biol Chem , 2005; 280(47): 39616–39626.
18 Nam SM, Lee MY, Koh JH, et al . Effects of NADPH oxidase inhibitor on diabetic nephropathy in OLETF rats: the role of reducing oxidative stress in its protective property. Diabetes Res Clin Pract , 2009; 83(2): 176–182.
19 Suzuki D, Toyoda M, Yamamoto N, et al . Relationship between the expression of advanced glycation end-products (AGE) and the receptor for AGE (RAGE) mRNA in diabetic nephropathy. Intern Med , 2006; 45(7): 435-441.
20 Matsui T, Yamagishi S, Takeuchi M, et al . Irbesartan inhibits advanced glycation end product (AGE)-induced proximal tubular cell injury in vitro by suppressing receptor for AGEs (RAGE) expression. Pharmacol Res , 2010; 61(1): 34-39.
21 Kim YS, Kim J, Kim CS, et al . KIOM-79,an Inhibitor of AGEs-Protein Cross-linking, Prevents Progression of Nephropathy in Zucker Diabetic Fatty Rats. Evid Based Complement Alternat Med , 2009; [Epub ahead of print] .
22 Taneja D, Thompson JC, Wilson PG, et al . Reversibility of renal injury with cholesterol lowering in hyperlipidemic diabetic mice. J Lipid Res , 2010; [Epub ahead of print].
23 Jiang T, Wang XX, Scherzer P, et al . Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy. Diabetes , 2007; 56(10): 2485–2493.
24 Mohan S, Reddick RL, Musi N, et al . Diabetic eNOS knockout mice develop distinct macro- and microvascular complications. Lab Invest , 2008; 88(5):515-528.
25 Hargrove GM, Dufresne J, Whiteside C, et a1. Diabetes mellitus increases endothelin-1 gene transcription in rat kidney. Kidney Int , 2000; 58(4): 1534—1545.
26 Isermann B, Vinnikov IA, Madhusudhan T, et a1. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med , 2007; 13(11): 1349-1358.
27 Nacira S, Meziani F, Dessebe O, et a1. Activated protein C improves lipopolysaccharide-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress. Crit Care Med , 2009; 37(1): 246-255.
28 Xue M, March L, Sambrook PN, et a1. Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: relevance to inflammation in rheumatoid arthritis. Arthritis Rheum , 2007; 56(9): 2864-2874.
29 Zhang Z, Peng H, Chen J, et a1. MicroRNA-21 protects from mesangial cell proliferation induced by diabetic nephropathy in db/db mice. FEBS Lett , 2009; 583(12): 2009-2014.
30 Kato M, Zhang J, Wang M, et a1. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-betainduced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A , 2007; 104(9): 3432–3437.
31 Miyauchi M, Toyoda M, Kobayashi K, et al . Hypertrophy and loss of podocytes in diabetic nephropathy. Inter Med , 2009; 48(18): 1615-1620.
32 Ruster C, Bondeva T, Franke S, et al . Angiotensin II upregulates RAGE expression on podocytes: role of AT2 receptors. Am J Nephrol , 2009; 29(6): 538-50.
33 Ikezumi Y, Suzuki T, Karasawa T, et al . Activated macrophages down-regulatepodocyte nephrin and podocin expression via stress-activated protein kinases.Biochem Biophys Res Commun , 2008; 376(4): 706-711.
34 Menini S, Iacobini C, Oddi G, et al . Increased glomerular cell (podocyte) apoptosis in rats with streptozotocin-induced diabetes mellitus: role in the development of diabetic glomerular disease. Diabetologia , 2007; 50(12): 2591-2599.
35 Wei XF, Zhou QG , Hou FF, et al . Advanced oxidation protein products induce mesangial cell perturbation through PKC-dependent activation of NADPH oxidase. Am J Physiol Renal Physiol , 2009; 296(2):F427-437.
36 Berthier CC, Zhang H, Schin M, et al . Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes , 2009; 58(2): 469-477.
37 Nishiyama A, Nakagawa T, Kobori H, et al . Strict angiotensin blockade prevents the augmentation of intrarenal angiotensin II and podocyte abnormalities in type 2 diabetic rats with microalbuminuria. J Hypertens , 2008; 26(9): 1849–1859.
38 Matsuia T, Yamagishia S, Takeuchib M, et a1. Irbesartan inhibits advanced glycation end product(AGE)-induced proximal tubular cell injury in vitro by suppressing receptor for AGEs (RAGE) expression. Pharmacol Res , 2010; 61(1): 34-39.
39 Mauer M, Zinman B, Gardiner R, et a1. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med , 2009; 361(1): 40-51.
40高苹,吴小燕,水华,等.氟伐他汀对血管紧张素Ⅱ诱导的大鼠肾小管上皮细胞核因子κB活性的影响.中华肾脏病杂志,2009; 25(2): 134-138.
41 Weissgarten J, Berman S, Efrati S, et a1. Apoptosis and proliferation of cultured mesangial cells isolated from kidneys of rosiglitazone—treatedpregnant diabetic rats. Nephrol Dial Transplant , 2006; 21(5): 1198—1204.
42 Kim MK, Ko SH, Baek KH, et al . Long-term effects of rosiglitazone on the progressive decline in renal function in patients with type 2 Diabetes. Korean J Intern Med , 2009; 24(3): 227-232.
43张燕,王威,关广聚,等.霉酚酸酯及缬沙坦对糖尿病大鼠足细胞的保护机制研究.中华肾脏病杂志, 2007; 23(9): 583-588.
44 Xiao S, Jin H, Korn T, et al . Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol , 2008; 181(4): 2277-2284.
45黄金平,陈星华,丁国华,等.全反式维甲酸对糖尿病大鼠足细胞损伤的保护作用.中华肾脏病杂志, 2006; 22(2): 545-548.
46 Yuan J, Jia RH, Bao Y, et a1. Beneficial effects of spironolactone on glomerular injury in streptozotocin-induced diabetic rats. J Renin Angiotensin Aldosterone Syst , 2007; 8(3): 118-126.
1. Masatoshi Kuratsune,Takao Masaki,Takayuki Hirai,et al. Signal transducer and activator of transcription 3 involvement in the development of renal interstitial fibrosis after unilateral ureteral obstruction.Nephrology,2007,(12):565–571.
2. Li J,Qu X,Bertram JF. Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induceddiabetic mice. Am J Pathol.2009,175 (4):1380-8.
3. Nicolas Picard ,Oliver Baum, Alexander Vogetseder, et al. Origin of renal myofibroblasts in the model of unilateral ureter obstruction in the rat . Histochem Cell Biol,2008,(130):141–155.
4. Ogatay, Ishidoya S,Fukuzaki A,et al. Upregulated expression of transforming growth factor beta , typeⅣcollagen , and plasminogen activator inhibitor-l mRNA are decreased after release of unilateral ureteral obstruction .Tohoku J EXPMed,2002,197(3):159—168.
5.衣利,舒贵扬,陈友明,等.转化生长因子β1在肾间质纤维化大鼠模型中的表达及意义.福建医药杂志,2007,29(4):67-69.
6. LIU LD,SHIH J,JIAN GL,et al. The repairing effect of a recombinant human connective-tissue growth factor in a burn-wounded rhesus-monkey (Macaca mulatta) model. Biotechnol Appl Biochem, 2007, 47 (2):105-112.
7. Tan XY, Zheng FL, Zhou QG.et al. Effect of bone morphogenetic protein-7 on monocyte chemoattactant protein-1 induced epithelial-myofibroblast transition and TGF–beta1-Smad3 signaling pathway of HKC cells. Zhonghua Yi Xue Za Zhi, 2005, 85 (37):2607-12.
8.赵班,李慧凛,连耀国,等.MCP-1诱导的肾小管上皮-间充质细胞转化与整合素连接激酶表达变化的关系.北京医学,2009,31(3):150-154.
9.颜润.血小板源性生长因子-B在肾间质纤维化模型大鼠肾组织中的表达及意义.贵州医药,2009,33(6):486-489.
10. Wu LL, Cox A. Transforming growth factor-βand renal injury following subtotal nephrectomy in the rat. Kidney Int,2007, 51:1553-1567.
11. Zhan Y, Brown C, Maynard E, et al.Ets-1 is a critical regulator of AngⅡ-mediated vascular inflammation and remodeling. J Clin Invest,2005,115(9):2508-2516.
12. Pearse DD,Tian RX, Nigro J,et al. Angiotensin II increases the expression of the transcription factor ETS-1 in mesangial cells. Am J Physio Renal Physiol, 2008,294 (5):F1094-1100.
13. A bbat M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage. J Am Soc Nephrol,2006,17(11):2974-2984.
14.夏运成,聂静,李志兰,等.血浆凝血酶敏感蛋白-1在肾间质纤维化中的表达.中南大学学报(医学版),2009,34(8):796-802.
15. Nakajima H, Takenaka M , Kaimori JY, et al. Activation of the signal transducer and activator of transcription signaling pathway in renal proximal tubular cells by albumin. J Am Soc Nephrol,2004, 15(2):276-285.
16.卢思广,沈琪.肾小管周围毛细血管在小管间质纤维化中的作用.实用儿科临床杂志,2007,22(17):1283-1286.
17. Debra F. Higgins, Kuniko Kimura, Wanja M. Bernhardt, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. The Journal of Clinical Investigation,2007,12(117):3810-3820.
18. Ya ng J, Ju W, Zeng FQ. Experimental study of the effect of L-arginine to prevent the progression of tubulointerstitial fibrosis in obstructive uropathy. Journal of Clinical Urology ,2008,23 (4):314-316.
19.王琳娜,陶立坚,宁旺斌.依那普利对单侧输尿管梗阻大鼠肾间质纤维化的防治作用.中南大学学报(医学版),2008,33(9):841-848.
20.周姗姗,傅君舟,郭群英,等.不同剂量氯沙坦对防治肾间质纤维化效果的影响.实用医学杂志,2007,23(8):1127-1130.
21.李英,段惠军,张涛,等.缬沙坦对高糖上调系膜细胞细胞外调节蛋白激酶表达的影响.中华肾脏病杂志,2007,23(2):101-105.
22.刘蒙,宋恩峰,骆小娟.厄贝沙坦对单侧输尿管梗阻大鼠肾间质纤维化的影响.医药导报,2009,28(10):1258-1261.
23.孙彬,王宁宁,何伟春,等.雷帕霉素对肾间质成纤维细胞Notch1/Jagged1信号通路及FN表达的影响.南京医科大学学报自然科学版,2006,26:829-833.
24.李慧凛,郑法雷,赵班.雷帕霉素对人肾小管上皮-肌成纤维细胞转化的抑制作用.基础医学与临床,2007,27:635-642.
25.王明军.来氟米特阻抑UUO大鼠肾间质纤维化的实验研究.广西医科大学学报,2007,24(2):202-204.
26. Takekazu K, Atsushi Y, Nobuyoshi I, et al. The therapeutic effects of Rho-ROCK inhibitors on CNS disorders. Ther Clin Risk Manag, 2008, 3(4):605-615.
27. Wang CY, Liu PY, James KL. Pleiotropic effects of statin therapy: Molecular mechanisms and clinical results. Trends Mol Med, 2008,14(1):37-44.
28.鲁盈,杨汝春,张迎华,等.白三烯受体拮抗剂对阿霉素肾病大鼠肾间质纤维化的干预作用及其机制研究.浙江医学,2008,30(11):1169-1179.
29. D.L. Andress. Vitamin D in chronic kidney disease: a systemic role for selective Vitamin D receptor activation. Kidney Int,2006,69:33–43.
30. Xiaoyue T, Yingjian L, Youhua L. Therapeutic role and potential mechanisms of active Vitamin D in renal interstitial fibrosis. Journal of Steroid Biochemistry & Molecular Biology,2007,103:491–496.
31. Eduardo Achar, Thiago T.Maciel, Carlos F. Collares. Amitriptyline attenuates interstitial inflammation and ameliorates the progression of renal fibrosis. Kidney International,2009,75:596–604.
32.刘蔚,何晓峰,赵晓琴,等.甲磺酸伊马替尼对单侧输尿管梗阻小鼠肾脏间质纤维化的影响.华中科技大学学报(医学版),2008,37(5):595-599.
33.方展,朱忠华,张春,等.螺内酯对梗阻性肾病大鼠肾间质纤维化的防治作用.中华肾脏病杂志,2006,22,(1):50-52.
34.林沁,马骥,顾勇,等.罗格列酮对单侧输尿管梗阻大鼠肾间质纤维化的保护作用及其机制.福州总医院学报,2005.6(12)120-122.
35. Shihab FS, Bennett WM, Yi H ,et al. Effect of pirfenidone on apoptosis-regulatory genes in chronic cyclosporine nephrotoxicity. Transplantation,2005, 79:419–426.
36.陶静莉,梁东,刘华锋,等.特异性NF-κB抑制剂对单侧输尿管梗阻大鼠肾间质纤维化的治疗作用.中国药理学通报,2008,24(4):539-542.
37. Ivica Grgic, Eva Kiss, Brajesh P. Kaistha. Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels. PNAS, 2009,106:14518-14523.
38. Jeong-Han Kang, Hyun-Ji Cho, In-Seon Lee, et al. Comparative proteome analysis of TGF-b1-induced fibrosis processes in normal rat kidney interstitial fibroblast cells in response to ascofuranone . Proteomics,2009,9:4445–4456.
39. Xisheng X, Feiyan L, Hengchuan L, et al. LSKL,a Peptide Antagonist of Thrombospondin-1,Attenuates Renal Interstitial Fibrosis in Rats with Unilateral Ureteral Obstruction. Arch Pharm Res,2010,33(2):275-284.
40.高志卿,康豪鹏,张俊,等.补肾活血方对肾间质纤维化大鼠肾组织中血小板衍生生长因子蛋白表达的影响.中华中医药杂志,2010,25(2):296-298.
41.张万超,马爱景,付平,等.肾纤复元胶囊对单侧输尿管梗阻大鼠模型肾间质纤维化的抑制作用及机制探讨.西部医学,2008,20(2):237-241.
42.刘莎,张丹,张义兵.真武壮肾汤对单侧输尿管梗阻大鼠肾间质纤维化防治的实验研究.中国当代医药,2009,16(15):48-49.
43.项琼,宋恩峰,贾汝汉,等.泽兰对单侧输尿管梗阻大鼠肾间质纤维化的影响.中国中西医结合肾病杂志,2009,10(3):197-200.
1. Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized o immunomodulator. Nat Med,2000,6 (12) :1399-1402.
2. Massy ZA, Kim Y, Guijarro C, et al. Low-density lipoprotein-induced expression of interleukin-6,a marker of human mesangial cell inflammation: effects of oxidation and modulation by lovastatin. Biochem Biophys Res Commun,2000,267 (2) 536-540.
3. Heusinger RJ, Fischer B, Goppelt SM, et al. Differential effects of simvastatin on mesangial cells. Kidney Int,2004,66 (1) :187-195.
4. Bussolati B, Deregibus MC, FonsatoV,et al. Statins prevent ox-idized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol3 kinase/AKT- signaling pathway.J Am Soc Nephrol,2005,16 (7) :1936-1947.
5. Vieira JM Jr, Rodrigues LT, Mantovani E, et al. Statin monotherapy attenuates renal injury in a salt-sensitive hypertension model of renal disease. Nephron Physiol,2005,101 (4) :82-91.
6. Vasantha K, Lixia Z, Hui P,et al. Targeting of RhoA/ROCK Signaling Ameliorates Progression of Diabetic Nephropathy Independent of Glucose Control. Diabetes,2008, 57(3):714–723.
7. Danesh FR, Sadeghi MM, Amro N, et al. 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase p21 signaling pathway: Implications for diabetic nephropathy. PNAS,2002,99(12):8301-8305.
8 Singh R, Alavi N, Singh AK, et al. Role of angiotensin II in glucose-Induced Inhibition of mesangial matrix degradation.Diabetes, 1999,48(10):2066-2073.
9. Banes-Berceli AK, Shaw S, Ma G,et al.Effect of simvastatin on high glucose- and angiotensin II-induced activation of the JAK/STAT pathway in mesangial cells. Am J Physiol Renal Physiol,2006,291(1): 116–121.
10. Amiri F, Shaw S, Wang X, et al. Angiotensin II activation of the JAK/STAT pathway in mesangial cells is altered by high glucose. Kidney Int.2002, 61(5):1605–1616.
11. Banes AK, Shaw S, Jenkins J, et al. Angiotensin II blockade prevents hyperglycemia-induced activation of JAK and STAT proteins in diabetic rat kidney glomeruli. Am J Physiol Renal Physiol.2004, 286(4): 653–659.
12. Wang X, Shaw S, Amiri F, et al.Inhibition of the JAk/STAT signaling pathway prevents the high glucose-induced increase in tgf-beta and fibronectin synthesis in mesangial cells. Diabetes,2002,51(12): 3505–3509.
13. Kobayashi T, Inoue T, Okada H, et al. Connective tissue growth factor mediates the profibrotic effects of transforming growth factor-beta produced by tubular epithelial cells in response to high glucose. Clin Exp Nephrol, 2005,9(2):114-121.
14. Lam S,Geest RN, Verhagen NA, et al. Connective tissue growth factor and igf-I are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose.Diabetes,2003,52(12):2975-2983.
15. Kim SI ,Kim HJ ,Han DC ,et al . Effect of lovastatin on small GTP binding proteins and on TGF-?1 and fibronectin expression. Kidney Int ,2000 ,58 (Suppl 77) ,S88~S92
16. Essig M, Vrtovsnik F, Venguyen G. Lovastatin modulates in vivo and in vitro the plasminogen activator/plasmin system of rat proximal tubular cells: role of geranylgeranylation and Rho proteins. J Am Soc Nephrol, 1998,9:1377-1388.
17. Nagatoya K, Moriyama T, Kawada N, et al. Y-27632 prevents tubulointerstitialfibrosis in mouse kidney with unilateral ureteral obstruction. Kidne y Int, 2002,61(5):1684-1695.
18. Patel S, Takagi KI, Suzuki J,et al.RhoGTPase activation is a key step in renal epithelial mesenchymal transdifferentiation. J Am Soc Nephrol, 2005,16(7): 1977–1984.
19. Fujii M, Inoguchi T, Maeda Y,et al. Pitavastatin ameliorates albuminuria and renal mesangial expansion by downregulating NOX4 in db/db mice. Kidney Int, 2007,72(4):473–480.
20. Nakamura T, Sugaya T, Kawagoe Y et al. Effect of pitavastatin on urinary liver-type fatty acid-binding protein levels in patients with early diabetic nephropathy. Diabetes Care,2005,28(11):2728–2732.
21. Marshall SM. The podocyte: a potential therapeutic target in diabetic nephropathy? Curr Pharm Des, 2007,13(26):2713-2720.
22. Blanco S ,Vaquero M, Gomez-Guerrero C, et al. Potential role of angiotensin-converting enzyme inhibitors and statins on early podocyte damage in a model of type 2 diabetes mellitus , obesity , and mild hypertension. Am J Hypertens, 2005,18(4):557-565.
23. Shibata S, Nagase M, Fujita T, et al.Fluvastatin ameliorates podocyte injury in proteinuric rats via modulation of excessive Rho signaling.J Am Soc Nephrol,2006,17(3):754–764.
24. Gojo A, Utsunomiya K, Taniguchi K,et al. The Rho-kinase inhibitor, fasudil, attenuates diabetic nephropathy in streptozotocin-induced diabetic rats. Eur J Pharmacol,2007,568(1-3):242-247.
25. Chow FY,Nikolic-Paterson DJ,Ozols E,et al. Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice.Kidney Int,2006,69(1), 73–80.
26. Lamhamedi-Cherradi SE, Zheng S, Hilliard BA, et al. Transcriptional regulation of type 1 diabetes by NF - kappa B. J Immunol, 2003, 171(9): 4886 - 4892.
27. Kim SI, Han DC, Lee HB. Lovastatin inhibits transforming growth factorβ1 expression in diabetic rat glomeruli and cultured rat mesangial cells. J Am Nephrol, Rho-associated kinase, Rho-associated kinase,2000, 11(1):80-87.
【1】Koh N, Fujimori T, Nishiguchi S , et al . Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun, 2001, 280(4): 1015 - 1020.
【2】Yamada Y, Ando F, Niino N, et al. Association of polymorphisms of the androgen receptor and klotho genes with bone mineral density in Japanese women. J Mol Med, 2005, 83(1) : 50–57.
【3】Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice bythe hormone Klotho. Science, 2005, 309(5742) : 1829–1833.
【4】Duce JA, Podvin S, Hollander W, et al. Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey. Glia, 2008, 56(1) : 106–117.
【5】Vonend O, Apel T, Amann K, Sellin L, et al. Modulation of gene expression by moxonidine in rats with chronic renal failure. Nephrol Dial Transplant. 2004, 19(9) : 2217–2222.
【6】Kuwahara N, Sasaki S, Kobara M, et al. HMG-CoA reductase inhibition improves anti-aging klotho protein expression and arteriosclerosis in rats with chronic inhibition of nitric oxide synthesis. Int J Cardiol, 2008, 123(2) : 84–90.
【7】Haruna Y, Kashihara N, Satoh M, et al. Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc. Natl. Acad. Sci. USA, 2007. 104(7) : 2331–2336.
【8】Sugiura H, Yoshida T, Tsuchiya K, et al. Klotho reduces apoptosis in experimental ischaemic acute renal failure. Nephrol Dial Transplant,2005, 20(12): 2636-45.
【9】Wang Y, Sun Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage. Hypertension, 2009, 54(4): 810-817.
【10】Saito Y, Kurabayashi M, Nakamura T, et al. Klotho gene and endothelial function. Nippon Ronen Igakkai Zasshi, 2006, 43(3): 342-344.
【11】Hesse M, Frohlich LF, Zeitz U, et al. Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Bio,l 2007, 26(2) : 75–84.
【12】Liu H, Fergusson MM, Castilho RM, et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science, 2007, 317(5839) : 803–806.
【13】Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature, 2006, 444(7120) : 770–774.
【14】Medici D, Razzaque MS, Deluca S, et al. FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis. J Cell Biol, 2008, 182(3) : 459–465.
【15】Nakatani T, Sarraj B, Ohnishi M, et al. In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) -mediated regulation of systemic phosphate homeostasis. FASEB J, 2009,23 (2):433-441.
【16】Kurosu H, Ogawa Y, Miyoshi M, et al.Regulation of Fibroblast GrowthFactor-23 Signaling by Klotho.J Biol Chem. 2006 ,281(10): 6120-6123.
【17】Yamamoto M, Clark JD, Pastor JV, et al. Regulation of oxidative stress by the anti-aging hormone klotho.J Biol Chem, 2005 ,280 (45): 38029-34.
【18】Kirstetter P, Anderson K, Porse BT, et al. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat. Immunol, 2006, 7(10): 1048–1056.
【19】Kuro-o, M. Klotho as a regulator of oxidative stress and senescence. Biol Chem, 2008, 389(3): 233–241.
【20】de Oliveira RM. Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway. FEBS Lett, 2006, 580(24): 5753–5758.
【21】Rakugi H, Matsukawa N, Ishikawa K, et al. Anti-oxidative effect of Klotho on endothelial cells through cAMP activation. Endocrine, 2007, 31(1): 82–87.
【22】Imai M, Ishikawa K, Matsukawa N, et al. Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression. Endocrine, 2004, 25 (3): 229–234.