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

Abstract

SUMMARY: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 ET A -receptor blockers (ET A -RB) on renal damage are controversial and have rarely been investigated in type 2 diabetes. We compared the influence of the selective ET A -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-␤, 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 ET A -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 ET A -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 ET A -RB. Treatment with ACE-i or ET A -receptor antagonist resulted in less structural and functional alterations, but the ET A -RB was inferior to the ACE-i. This is particularly the case for podocyte changes pointing to angiotensin II-dependent pathomechanisms. (Lab Invest 2003, 83:1267-1277.

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes

“…The other organs were removed after continuous perfusion with glutaraldehyde for morphometric investigations. 1 The glutaraldehyde-perfused kidney was dissected in a plane perpendicular to the interpolar axis, yielding slices of 1 mm width. In all, 10 small pieces of this kidney were selected by area-weighted sampling for embedding in Epon-Araldite.…”

“…In recent years, the efficacy of pharmacological blockade of the renin-angiotensin system in diabetic nephropathy has been documented in experimental 1 and clinical studies. 2 Although this intervention is effective, it fails to abrogate progression of renal disease consistently and completely.…”

Comparison of renal morphology in the Streptozotocin and the SHR/N-cp models of diabetes

“…20 Tubulointerstitial and vascular damage was assessed on PASstained paraffin sections at a magnification of  100 using a similar scoring systems as described in detail. 20,22 Glomerular geometry Briefly, glomerular geometry was analyzed as follows: Volume density (V V ) of glomeruli and area density of glomerular tuft (A AT ) were measured by point counting according to P P ¼A A ¼V V at a magnification of  400 on HE sections. 23 The total area of glomerular tuft (A T ) was then determined as A T ¼A AT ÂA cortex .…”

“…Paraffin sections were prepared and were incubated with the following antibodies using the avidin-biotin method: PCNA (proliferating cell nuclear antigen; a-PCNA monoclonal mouse, Immunotech, Marseille, France), P27 KIP1 (a-P27 polyclonal rabbit, Santa Cruz, CA, USA), TGFb 1 (anti-TGF-b 1 , rabbit polyclonal IgG, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and desmin (a-desmin monoclonal mouse, Capinteria, CA, USA). Thick cryostat sections (5 mm) were prepared and the sections were incubated with the following antibodies using the avidin-biotin method: 20 fibronectin (a-fibronectin polyclonal rabbit, Sigma-Aldrich Chemie GmbH, Steinheim, Germany), endothelin (a-ET-1 polyclonal rabbit, Biotrend, Cologne, Germany) and PDGF-AB (platelet-derived growth factor; a-PDGF-AB polyclonal goat, Upstate Biotechnology Inc., Waltham, USA). Optimal staining concentration was evaluated testing different dilution series.…”

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

“…186,187 Several human studies demonstrated a correlation between plasma or urinary levels of ET-1 and markers of DN, such as hyperfiltration, mesangial expansion, macro-and/or microalbuminuria, and uremia. [188][189][190][191][192] In addition, interventional studies using endothelin-receptor-blockers have yielded encouraging results [193][194][195][196][197][198] in rodent models of DMT1 195,198 or DMT2. 196,197 Honing et al 199 reported reversal of proteinuria in 10 patients with DMT1 after treatment with the ETantagonist; atrasentan for 12 weeks.…”