Pathophysiological roles of Ca(2+) overload via the Na(+)/Ca(2+) exchanger and endothelin-1 overproduction in ischaemia/reperfusion-induced acute renal failure.

Using Na + /Ca 2+ exchanger (NCX1)-deficient mice, the pathophysiological role of Ca 2+ overload via the reverse mode of the Na + /Ca 2+ exchanger in ischaemia/reperfusion-induced renal injury was investigated. Since NCX1 -/- homozygous mice die of heart failure before birth, we utilized NCX1 +/- heterozygous mice. The ischaemia/reperfusion-induced renal dysfunction in heterozygous mice were significantly attenuated compared with cases in wild-type mice. Also, histological renal damage such as tubular necrosis and proteinaceous casts in tubuli in heterozygous mice were much less than that in wild-type mice. Ca 2+ deposition in necrotic tubular epithelium was observed more markedly in wild-type than in heterozygous mice. The increase in renal endothelin-1 (ET-1) content was significantly greater in wild-type than in heterozygous mice, and this reflected the difference in immunohistochemical ET-1 localization in necrotic tubular epithelium. We conclude that Ca 2+ overload via the reverse-mode of Na + /Ca 2+ exchange, followed by renal ET-1 overproduction, plays an important role in the pathogenesis of ischaemia/reperfusion-induced acute renal failure.