Submitted on October 12, 2007
Accepted on January 29, 2008
NMDA Receptor Blocker Ameliorates Ischemia/Reperfusion-Induced Renal Dysfunction in Rat Kidneys
Chih-Ching Yang1, Chiang-Ting Chien2, Ming-Hsiou Wu3, Ming Chieh Ma4, and Chau-Fong Chen5*
1 Department of Physiology, College of Medicine of National Taiwan University, Taipei, Taiwan - Republic of China
2 Department of Medical Research, College of Medicine of National Taiwan University, Taipei, Taiwan - Republic of China
3 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan - Republic of China
4 School of Medicine, Fu-Jen Catholic University, Hsinchuang, Taiwan - Republic of China
5 Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan - Republic of China
* To whom correspondence should be addressed. E-mail: chfochen{at}ha.mc.ntu.edu.tw.
Background: N-methyl-D-aspartate (NMDA) receptor activated by glutamate/glycine is located in the kidney. The abundance of the NMDA receptor subunit, NR1, was increased in the damaged renal tubules. We explored whether NMDA receptors participate in ischemia/reperfusion induced renal dysfunction in the rat. Methods: With western blotting analysis and renal functional assay, we evaluated NMDA receptor expression and functional role in the Female Wistar rat kidney after 45 min of unilateral ischemia followed by 24 h of reperfusion. The effects of intrarenal NMDA receptor agonist and antagonist on renal blood flow (RBF), glomerular filtration rate (GFR), urine volume (UV), sodium (UNaV) and potassium (UKV) excretion were determined. Results: NMDA NR1 is present in the glomeruli, brush border membrane, and outer medulla, but not in cortex and inner medulla. Homogenous distribution of non-NMDA GluR2/3, sparse kainate KA1 and undetectable group I of metabotropic glutamate receptor are noted in the control kidney. Ischemia/reperfusion kidneys are demonstrated with enhanced renal NR1, not GluR2/3 expression and associated with decreased GFR/RBF and natriuretic/diuretic responses. Intrarenal NMDA agonist reduced GFR, UV, UNaV and UKV, but had no effect on blood pressure and RBF in sham-control and ischemia/reperfusion kidneys. NMDA antagonist D(-)-2-Amino-5-phosphonopentanoic acid (D-AP-5) treatment completely abolished NMDA-induced renal dysfunction. D-AP-5 treatment significantly ameliorated ischemia/reperfusion induced glomerular and tubular dysfunction by recovering the decreased GFR, UV, and UNaV. Conclusion: Ischemia/reperfusion upregulates renal NMDA NR1 receptor expression leading to the reduction of glomerular and tubular function in the kidney. NMDA antagonist can ameliorate ischemia/reperfusion induced renal dysfunction.
