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

Abstract

Experimental findings suggest that the obese Zucker rat (OZR) is a model of type 2 diabetes-related nephropathy with several metabolic abnormalities. However, the exact mechanisms by which these factors cause early glomerulosclerosis and proteinuria remain unclear. Furthermore, structural abnormalities and regulation of podocytes have recently emerged as prominent underlying factors in proteinuria. The aim of this study was to evaluate the potential role of angiotensin-converting enzyme inhibitors and statins on early podocyte damage in an experimental model of type 2 diabetes mellitus. We used OZR to evaluate some of the pathogenic mechanisms and the effects of two drugs, an angiotensin-converting enzyme (ACE) inhibitor (quinapril) and a statin (atorvastatin), involved in the development of proteinuria and especially podocyte damage. We studied glomerular and tubulointerstitial injury by assessing inflammation mediators (murine monoclonal antibody against CD68 [ED1+], interleukin-8 [IL-8], interferon-gamma-inducible protein 10 [IP-10]) and podocyte damage markers using desmin staining and electron microscopy. Glomerular lesions were correlated with cholesterol (r = 0.676), proteinuria (r = 0.804), triglycerides (r = 0.593), insulin (r = 0.345), creatinine (r = 0.266), and glucose (r = 0.245). In addition, podocytes from OZR showed positive staining for desmin. Use of the ACE inhibitor quinapril normalized proteinuria, cholesterol levels, glomerular lesions, and podocyte morphology. In contrast, atorvastatin ameliorated but did not normalize renal damage, with a partial reduction in desmin staining and podocyte morphology. Treatment with both drugs resulted in only a slight reduction in IL-8 and IP-10 in the tubulointerstitium. In the OZR, cholesterol was an important determinant of renal injury. Most notably, glomerulosclerosis in the OZR Is characterized by early podocyte damage and tubulointerstitial injury. In addition, our findings showed that quinapril primarily normalized podocyte morphology, whereas atorvastatin ameliorated renal lesions through the diminution of lipids and by its lipid-independent pleiotropic effect.