Simvastatin abates development of renal fibrosis in experimental renovascular disease

Abstract

Epithelial-to-mesenchymal transition contributes to renal fibrogenesis, which is regulated by profibrogenic and antifibrogenic mediators. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can prevent epithelial-to-mesenchymal transition in some models. Therefore, we tested the hypothesis that epithelial-to-mesenchymal transition participates in renal injury in porcine atherosclerotic renovascular disease and can be attenuated by simvastatin. Renal hemodynamics, function, and endothelial function were quantified in vivo in pigs after 12 weeks of combined hypercholesterolemia + renal artery stenosis without (n = 8) or with oral simvastatin supplementation (1.2 mg/kg, n = 6), and in controls (n = 8). Ex-vivo studies assessed renal immunoreactivity to fibrogenic factors and renal histology. Blood pressure, cholesterol levels, and basal renal function were similar in treated and untreated pigs with hypercholesterolemia + renal artery stenosis. Hypercholesterolemia + renal artery stenosis significantly upregulated renal transforming growth factor-beta signaling and elicited epithelial-to-mesenchymal transition, accompanied by glomerulosclerosis and renal fibrosis. Simvastatin did not affect smad 2/3 expression but upregulated expression of hepatocyte growth factor, bone morphogenetic factor-7, and smad 7 and prevented most of these renal structural and functional alterations. Furthermore, simvastatin improved renal blood flow response to endothelium-dependent challenge (+111.3 +/- 35.5 vs. -30.4 +/- 18.7 ml/min in untreated pigs, P < 0.05). Simvastatin upregulates inhibitors of transforming growth factor-beta signaling, attenuates epithelial-to-mesenchymal transition, and decreases renal fibrosis in hypercholesterolemia + renal artery stenosis. These lipid-lowering-independent effects result in improvement of renal function, suggesting clinically valuable potential for statins in preserving the stenotic kidney and limiting deterioration of renal function in atherosclerotic renovascular disease.