Renal disease progression in the rat is associated with a time-dependent upregulation of renal endothelin-1 (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 (n = 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.