KB-R7943, a selective Na+/Ca2+ exchange inhibitor, protects against ischemic acute renal failure in mice by inhibiting renal endothelin-1 overproduction

We investigated whether the preischemic or postischemic treatment with KB-R 7943, a novel and selective Na+/Ca2+ exchange inhibitor, has renal protecti ve effects in mice with ischemic acute renal failure (ARF). Ischemic ARF wa s induced by clamping the left renal pedicle for 45 min followed by reperfu sion, 2 weeks after contralateral nephrectomy. Renal function was markedly diminished 24 h after reperfusion. Preischemic treatment with KB-R7943 atte nuated the ARF-induced renal dysfunction. The ischemia/reperfusion-induced renal dysfunction was also overcome by postischemic treatment with KB-R7943 . Histopathologic examination of the kidneys of ARF mice revealed severe re nal damage such as tubular necrosis, proteinaceous casts in tubuli, and med ullary congestion. Histologically evident damage and Ca2+ deposition in nec rotic tubular epithelium were improved by preischemic treatment with KB-R79 43. In addition, preischemic treatment with KB-R7943 significantly suppress ed the increment of endothelin-1 (ET-1) content in the kidney at 2, 6, and 24 h after reperfusion. These findings suggest that Ca2+ overload via the r everse mode of Na+/Ca2+ exchange, followed by renal ET-1 overproduction, pl ays an important role in the pathogenesis of the ischemia/reperfusion-induc ed ARF. KB-R7943 may prove to be an effective therapeutic agent for cases o f ischemic ARF in humans.