Simvastatin abates development of renal fibrosis in experimental renovascular disease

Abstract

Background and objectives: 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.

Methods: 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.

Results: 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).

Conclusion: 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.