Vol. 304, Issue 1, 284-293, January 2003

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

Junji Yamashita, Satomi Kita, Takahiro Iwamoto, Masaya Ogata, Masanori Takaoka, Naoko Tazawa, Mitsunori Nishikawa, Koji Wakimoto, Munekazu Shigekawa, Issei Komuro and Yasuo Matsumura

Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka, Japan (J. Y., M. O., M. T., N. T., M. N., Y. M.); Department of Molecular Physiology, National Cardiovascular Center Research Institute, Osaka, Japan (S.K., T.I., M.S.); Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd., Osaka, Japan (K.W.); and Third Department of Internal Medicine, Chiba University School of Medicine, Chiba, Japan (I.K.)

Using Na⁺/Ca²⁺ exchanger (NCX1)-deficient mice, the pathophysiological role of Ca²⁺ 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 Ca²⁺ 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. Ca²⁺ 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 Ca²⁺ overload via the reverse mode of Na⁺/Ca²⁺ exchange, followed by renal endothelin-1 overproduction, plays an important role in the pathogenesis of ischemia/reperfusion-induced renal injury.