title: Attenuation of ischemia/reperfusion-induced renal injury in mice deficient in Na+/Ca2+ exchanger.
abstract: 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.
authors.affiliation: Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yamashita
authors.forename: Satomi
authors.initials: S
authors.lastname: Kita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Masaya
authors.initials: M
authors.lastname: Ogata
authors.forename: Masanori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Naoko
authors.initials: N
authors.lastname: Tazawa
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Nishikawa
authors.forename: Koji
authors.initials: K
authors.lastname: Wakimoto
authors.forename: Munekazu
authors.initials: M
authors.lastname: Shigekawa
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007677:Kidney Function Tests; D007686:Kidney Tubules, Distal / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019831:Sodium-Calcium Exchanger / Q000235:genetics* / Q000378:metabolism; D013552:Swine; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014882:Water-Electrolyte Balance / Q000235:genetics / Q000502:physiology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D019332:Endothelin-1; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D013890:Thiourea; D002118:Calcium