Nephrol Dial Transplant (1996) 11: 514-520
© 1996 European Renal Association-European Dialysis and Transplant Association
research-article
Influence of specific and non-specific endothelin receptor antagonists on renal morphology in rats with surgical renal ablation
1Department of Internal Medicine, University of Heidelberg Ludwigshafen, Rhein, Germany 2Department of Pathology, University of Heidelberg Ludwigshafen, Rhein, Germany 3Knoll AG Ludwigshafen, Rhein, Germany
Correspondence and offprint requests to: Correspondence and offprint requests to: A. Nabokov, Department of Internal Medicine, University of Heidelberg, Bergheimer Strasse 56a, D-69115 Heidelberg, Germany
BACKGROUND.: Studies in experimental models of chronic renal failure suggest an important role for the endothelin system in the development of renal scarring. Endothelin receptor (ETR) anatagonists interfere with progression, but it has not been resolved (i) whether this is true for all models of renal damage, (ii) to what extent the effect is modulated by systemic blood pressure and (iii) whether the effect is similar for ETAR and ETA/ETBR antagonists.
STUDY DESIGN.: 5/6 subtotal nephrectomy (SNX) by surgical ablation in male Sprague—Dawley rats. Comparison of ACE inhibitor Trandolapril (0.1 mg/kg/day), ETAR antagonist BMS 182874 (30 mg/kg/day) and ETAR/ETBR antagonist Ro 46-2005 (30 mg/kg/day) by gavage. Duration of the experiment eight weeks.
METHODS.: Systolic blood pressure by tail plethysmography. Perfusion fixation of kidneys and morphometric analysis ET-1 and ETA/ETBR by quantitative PCR.
RESULTS.: SNX caused a significant (P<0.01) increase of systolic blood pressure (170±8.6 mmHg) compared to sham operated controls (131±5.3 mmHg). Blood pressure was significantly (P<0.001) lower with Trandolapril (128±5.3 mmHg), but not with BMS 182874 (153±5.9 mmHg) or Ro 46-2005 (167±7.6 mmHg). Compared to sham operated rats (0.03±0.01) glomerulosclerosis index (GSI) was significantly (P<0.01) higher in the untreated SNX group (0.9±0.15). Significantly lower GSI was found in Trandolapril treated (0.29±0.04), BMS 182874 treated (0.36±0.05), and Ro 46-2005 treated animals (0.45±0.11). The effect of BMS 182874 was accompanied by lower tubulointerstitial damage index. Mean glomerular volume was dramatically increased (P<0.001) in SNX rats as compared to sham operated animals. This glomerular enlargement was partially prevented by Trandolapril (P<0.05), but not by either ETR antagonist. ET-1 mRNA tended to be higher in SNX irrespective of treatment, while ETAR and ETBR mRNA were significantly lower.
CONCLUSION.: Both specific (ETAR) and non-specific (ETA/ETBR) endothelin antagonists interfere with development of glomeruloscierosis by mechanisms which are, at least in part, independent of systemic blood pressure.
Keywords: glomerular hypertrophy; glomerulosclerosis; endothelin receptor antagonist; renal failure; subtotal nephrectomy
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