Blocking both type A and B endothelin receptors in the kidney attenuates renal injury and prolongs survival in rats with remnant kidney

Renal disease progression in the rat is associated with a time-dependent upregulation of renal endothelin-l (ET-1) gene expression and synthesis. We have previously demonstrated that endothelin A receptor subtype (ET(A)) blockade in rats with remnant kidney reduced signs of disease activity, suggesting that ET-1 exerts part of its deleterious effects on the kidney through ET(A). No data are available so far on the role of ET(B) receptor in progressive renal injury. We first studied renal ET(A) and ET(B) receptor gene expression in rats with remnant kidney on days 7, 30, and 120 after the surgical procedure. While renal expression of ET(A) was unaffected, ET(B) receptor gene was significantly upregulated with time in rats with remnant kidney, being 3.5-fold and sixfold higher than sham-operated rats at days 30 and 120. We also evaluated whether bosentan, a nonpeptidic ET(A) and ET(B) receptor antagonist, offered better protection against renal disease progression than reported for ET(A)-selective blockers and whether it improved survival in animals with renal ablation. Two groups of rats with renal mass reduction (0 = 11 each) were given bosentan 100 mg/kg/d orally or its vehicle (carboxymethyl cellulose) beginning day 7 after the surgical procedure and were followed until the death of the vehicle-treated animals. Sham-operated animals comprised the control group. Bosentan partially prevented increases in blood pressure and proteinuria, but had a remarkable protective effect on renal function and significantly prolonged animal survival. These data suggest that blocking both renal ET(A) and ET(B) receptors might have major implications in the treatment of human progressive nephropathies. (C) 1996 by the National Kidney Foundation, Inc.