Attenuation of Ischemia/Reperfusion-Induced Renal Injury in Mice Deficient in Na+/Ca2+ Exchanger
- Junji Yamashita1,
- Satomi Kita2,
- Takahiro Iwamoto2,
- Masaya Ogata1,
- Masanori Takaoka1,
- Naoko Tazawa1,
- Mitsunori Nishikawa1,
- Koji Wakimoto3,
- Munekazu Shigekawa2,
- Issei Komuro4 and
- Yasuo Matsumura1
- 1Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka, Japan (J. Y., M. O., M. T., N. T., M. N., Y. M.); 2Department of Molecular Physiology, National Cardiovascular Center Research Institute, Osaka, Japan (S.K., T.I., M.S.); 3Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd., Osaka, Japan (K.W.); and 4Third Department of Internal Medicine, Chiba University School of Medicine, Chiba, Japan (I.K.)
- Dr. Yasuo Matsumura, Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. E-mail:matumrh{at}gly.oups.ac.jp
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.
Footnotes
-
This work was supported by Grant-in-Aid for Scientific Research 12670098 (to Y.M.) and 12670102 (to T.I.) from the Ministry of Education, Science and Culture of Japan, and a Grant from the Cardiovascular Research Foundation (to T.I.).
-
DOI: 10.1124/jpet.102.039024
- Abbreviations:
- NCX1
- Na+/Ca2+exchanger
- KB-R7943
- 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate
- ARF
- acute renal failure
- ET-1
- endothelin-1
- PBS
- phosphate-buffered saline
- BUN
- blood urea nitrogen
- Uosm
- urinary osmolarity
- FENa
- fractional excretion of sodium
- Ccr
- creatinine clearance
- KHB
- Krebs-Henseleit buffer
- [Ca2+]i
- intracellular calcium concentration
- BSS
- balanced salt solution
- [Ca2+]o
- extracellular calcium concentration
- RIA
- radioimmunoassay
- DMEM
- Dulbecco's modified Eagle's medium
- LDH
- lactate dehydrogenase
- Pcr
- plasma creatinine concentration
- UF
- urine flow
- SK&F96365
- 1-[-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenyl]-1H-imidazole hydrochloride
- ABT-627
- [2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid]
- A-192621
- [2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid]
-
- Received May 15, 2002.
- Accepted October 1, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
