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.
Matsumura
Yasuo
Y
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. matumrh@gly.oups.ac.jp
Yamashita
Junji
J
Kita
Satomi
S
Iwamoto
Takahiro
T
Ogata
Masaya
M
Takaoka
Masanori
M
Wakimoto
Koji
K
Shigekawa
Munekazu
M
Komuro
Issei
I
D058186:Acute Kidney Injury / Q000209:etiology* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D019332:Endothelin-1 / Q000032:analysis / Q000096:biosynthesis*; D007150:Immunohistochemistry; D007668:Kidney / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*
D019332:Endothelin-1; D019831:Sodium-Calcium Exchanger; D002118:Calcium