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-R7943, a novel and selective Na+/Ca2+ exchange inhibitor, has renal protective effects in mice with ischemic acute renal failure (ARF). Ischemic ARF was induced by clamping the left renal pedicle for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function was markedly diminished 24 h after reperfusion. Preischemic treatment with KB-R7943 attenuated 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 renal damage such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion. Histologically evident damage and Ca2+ deposition in necrotic tubular epithelium were improved by preischemic treatment with KB-R7943. In addition, preischemic treatment with KB-R7943 significantly suppressed 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 reverse mode of Na+/Ca2+ exchange, followed by renal ET-1 overproduction, plays an important role in the pathogenesis of the ischemia/reperfusion-induced ARF. KB-R7943 may prove to be an effective therapeutic agent for cases of ischemic ARF in humans.
Department of Pharmacology, Osaka University, of Pharmaceutical Sciences, Takatsuki, Japan.
J
J
Yamashita
M
M
Ogata
M
M
Takaoka
Y
Y
Matsumura
D058186:Acute Kidney Injury / Q000517:prevention & control*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D019332:Endothelin-1 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007511:Ischemia / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D015427:Reperfusion Injury / Q000517:prevention & control; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D019332:Endothelin-1; D019831:Sodium-Calcium Exchanger; D013890:Thiourea; D002118:Calcium