Inhibitory effect of statins on renal epithelia-to-mesenchymal transition

被引:45
作者
Patel, Sharmila
Mason, Roger M.
Suzuki, Jun
Imaizumi, Atsushi
Kamimura, Takashi
Zhang, Zhi
机构
[1] Med Res Council Technol, Teijin Biomed Lab, London NW7 1AD, England
[2] Hammersmith Hosp, Imperial Coll London, Renal Med Sect, Fac Med, London, England
[3] Teijin Pharma Ltd, Inst Biomed Res, Tokyo, Japan
关键词
RhoA activation; Rac1; activation; small RhoGTPase; isoprenylation; epithelial-to-mesenchymal transition; statins; renal fibrosis;
D O I
10.1159/000094780
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background/Aim: Recent studies have suggested that statins may play a role in the protection against renal failure which is independent of cholesterol reduction. Activation of RhoGTPases is a key step in renal tubular cells' epithelial-to-mesenchymal transition (EMT) which contributes to renal interstitial fibrosis. We hypothesized that statins could act by inhibiting the synthesis of the isoprenoids, such as geranylgeranyl pyrophosphate, which is essential for membrane attachment and biological activity of RhoGTPases, RhoA and Rac1. Methods: Human proximal tubular epithelial cells (HK2) were used to examine the inhibitory effect of statins on EMT induced with medium conditioned by activated peripheral blood mononuclear cells. Results: Our study demonstrates that the statins lovastatin, simvastatin, and pravastatin inhibit HK2 cells to undergo EMT. Inhibition of EMT in HK2 cells with these statins resulted in a reduction of RhoA and Rac1 activation in both the cytoplasmic and membrane-bound forms, in preservation of the expression of the epithelial cell markers E-cadherin and cytokeratin-19, and in a decrease in Fn-EDA expression, a marker for the myofibroblast phenotype. The decreased levels of activated RhoA and Rac1 in both the cytoplasmic and membrane fractions of the cells were reversed by geranylgeranyl pyrophosphate and mevalonate, and thus attributable to the inhibition of isoprenylation of RhoGTPases by statins. Conclusion: This phenomenon could explain the beneficial effect of statins on EMT and on renal fibrosis prevention. Copyright (c) 2006 S. Karger AG, Basel.
引用
收藏
页码:381 / 387
页数:7
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