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: Junji Yamashita, Satomi Kita, Takahiro Iwamoto, Masaya Ogata, Masanori Takaoka, Naoko Tazawa, Mitsunori Nishikawa, Koji Wakimoto, Munekazu Shigekawa, Issei Komuro, Yasuo Matsumura
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 304 Issue 1 Pg. 284-93 (Jan 2003) ISSN: 0022-3565 [Print] United States
• PMID: 12490603 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
• Endothelin-1
• Sodium-Calcium Exchanger
• sodium-calcium exchanger 1
• Thiourea
• Calcium

Topics

• Animals
• Blood Urea Nitrogen
• Blotting, Western
• Calcium (metabolism)
• Cells, Cultured
• Endothelin-1 (metabolism)
• Immunohistochemistry
• Kidney (pathology)
• Kidney Diseases (genetics, metabolism, pathology)
• Kidney Function Tests
• Kidney Tubules, Distal (metabolism, pathology)
• Kidney Tubules, Proximal (metabolism, pathology)
• LLC-PK1 Cells
• Male
• Mice
• Mice, Knockout
• Reperfusion Injury (genetics, metabolism, pathology)
• Sodium-Calcium Exchanger (genetics, metabolism)
• Swine
• Thiourea (analogs & derivatives, pharmacology)
• Water-Electrolyte Balance (genetics, physiology)