Inhibitory Effect of Statins on Renal Epithelial-to-Mesenchymal Transition

Abstract

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.

Fasudil Inhibits Epithelial-Myofibroblast Transdifferentiation of Human Renal Tubular Epithelial HK-2 Cells Induced by High Glucose

“…23,39,40) Masszi et al reported that Rho plays a central role in TGF-β 1 -induced α-SMA expression during EMT, 39) and Patel et al 41) determined that RhoGTPase activation is a key step in renal EMT. The Rho/ROCK pathway generated significant interest as a key regulator in a variety of renal injury models, and may also play a critical role in many of the chronic complications of DM.…”

Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia/Reperfusion Injury and Chronic Rejection Through Microvascular Protection

“…42 Recent observations show that ECs contribute directly to myocardial fibrosis in a process of EndMT. 11 A similar phenomenon, epithelial-to-mesenchymal transition, occurs in kidney fibrosis; it involves TGF-␤1, 43 RhoA, 44 hypoxia, and HIF-1 45 and is inhibited by statins. 44 Here, we found that donor simvastatin treatment reduced cardiac allograft TGF-␤1 activation and fibrosis and that simvastatin also inhibited TGF-␤1-induced EndMT in vitro.…”

“…11 A similar phenomenon, epithelial-to-mesenchymal transition, occurs in kidney fibrosis; it involves TGF-␤1, 43 RhoA, 44 hypoxia, and HIF-1 45 and is inhibited by statins. 44 Here, we found that donor simvastatin treatment reduced cardiac allograft TGF-␤1 activation and fibrosis and that simvastatin also inhibited TGF-␤1-induced EndMT in vitro. Our results thus support the findings that cardiac allograft EC dysfunction may directly participate in myocardial fibrosis through EndMT.…”

Pharmacologic Targets and Peritoneal Membrane Remodeling

“…Statins have also shown to prevent EMT in tubular epithelial cells in vitro (63). Adding atorvastatin to the drinking water of nonuremic rats on PD preserved ultrafiltration and resulted in less thickening of the peritoneal membrane (64).…”