Attenuation of Ischemia/Reperfusion-Induced Renal Injury in Mice Deficient in Na+/Ca2+ Exchanger

Using Na + /Ca 2+ exchanger (NCX1)-deficient mice, the pathophysiological role of Ca 2+ overload via the reverse mode of NCX1 in ischemia/reperfusion-induced renal injury was investigated. Because NCX1 −/− homozygous mice die of heart failure before birth, we used NCX1 +/− heterozygous mice. NCX1 protein in the kidney of heterozygous mice decreased to about half of that of wild-type mice. Expression of NCX1 protein in the tubular epithelial cells and Ca 2+ influx via NCX1 in renal tubules were markedly attenuated in the heterozygous mice. Ischemia/reperfusion-induced renal dysfunction in heterozygous mice was significantly attenuated compared with cases in wild-type mice. 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. Increases in renal endothelin-1 content were greater in wild-type than in heterozygous mice, and this reflected the difference in immunohistochemical endothelin-1 localization in necrotic tubular epithelium. When the preischemic treatment with KB-R7943 was performed, the renal functional parameters of both NCX1 +/+ and NCX1 +/− acute renal failure mice were improved to the same level. These findings strongly support the view that Ca 2+ overload via the reverse mode of Na + /Ca 2+ exchange, followed by renal endothelin-1 overproduction, plays an important role in the pathogenesis of ischemia/reperfusion-induced renal injury.