BLOCKING BOTH TYPE-A AND TYPE-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-depende nt upregulation of renal endothelin-l (ET-1) gene expression and synth esis. We have previously demonstrated that endothelin A receptor subty pe (ET(A)) blockade in rats with remnant kidney reduced signs of disea se activity, suggesting that ET-1 exerts part of its deleterious effec ts on the kidney through ET(A). No data are available so far on the ro le of ET(B) receptor in progressive renal injury. We first studied ren al ET(A) and ET(B) receptor gene expression in rats with remnant kidne y on days 7, 30, and 120 after the surgical procedure. While renal exp ression 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 ev aluated whether bosentan, a nonpeptidic ET(A) and ET(B) receptor antag onist, offered better protection against renal disease progression tha n reported for ET(A)-selective blockers and whether it improved surviv al 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 p rocedure and were followed until the death of the vehicle-treated anim als. Sham-operated animals comprised the control group. Bosentan parti ally prevented increases in blood pressure and proteinuria, but had a remarkable protective effect on renal function and significantly prolo nged animal survival. These data suggest that blocking both renal ET(A ) and ET(B) receptors might have major implications in the treatment o f human progressive nephropathies. (C) 1996 by the National Kidney Fou ndation, Inc.