Renal Damage in the SHR/N-cp Type 2 Diabetes Model: Comparison of an Angiotensin-Converting Enzyme Inhibitor and Endothelin Receptor Blocker

Abstract

The pathomechanisms that cause renal damage in diabetes have not been completely clarified. Treatment with angiotensin-converting enzyme inhibitors (ACE-i) is highly effective but fails to completely prevent end-stage renal disease. The effects of ETA-receptor blockers (ETA-RB) on renal damage are controversial and have rarely been investigated in type 2 diabetes. We compared the influence of the selective ETA-RB LU135252 and the ACE-i Trandolapril on renal structure in the SHR/N-cp rat model of type 2 diabetes. Three-month-old male SHR/N-cp rats were left untreated or received daily either Trandolapril or LU135252. The experiment was terminated after 6 months. The glomerulosclerosis index; tubulointerstitial damage index; and glomerular geometry, glomerular cell number, and capillary density were investigated. Proliferating cell nuclear antigen and desmin expression of podocytes, renal mRNA expression of endothelin (ET-1) and transforming growth factor-β, blood pressure, and urine albumin excretion were measured. The glomerulosclerosis index was significantly higher in untreated diabetic animals than in the groups that were treated with ACE-i and ETA-RB. There were analogous changes in tubulointerstitial damage index. Treatment with either substance comparably lowered urinary albumin excretion in diabetic SHR/N-cp. Podocyte and endothelial cell numbers per glomerulus decreased in untreated diabetic animals; this was prevented by the ACE-i but not by the ETA-RB. Glomerular capillary length density was lower in SHR/N-cp, and this was normalized by ACE-i only. Increased expression of desmin and proliferating cell nuclear antigen expression of podocytes in the SHR/N-cp was abrogated by ACE-i but not by ETA-RB. Treatment with ACE-i or ETA-receptor antagonist resulted in less structural and functional alterations, but the ETA-RB was inferior to the ACE-i. This is particularly the case for podocyte changes pointing to angiotensin II–dependent pathomechanisms.