NMDA receptor blocker ameliorates ischemia-reperfusion-induced renal dysfunction in rat kidneys.
N-methyl-d-aspartate (NMDA) receptor activated by glutamate/glycine is located in the kidneys. The NMDA receptor subunit NR1 is increased in damaged renal tissue. This study explored the role of NMDA receptors in ischemia-reperfusion-induced renal dysfunction in rats. With Western blot analysis and renal functional assay, NMDA receptor expression was evaluated, as well as its functional role in female Wistar rat kidneys 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 (U(Na)V), and potassium (U(K)V) excretion were determined. NMDA NR1 was present in the glomeruli, brush-border membrane, and outer medulla but not in the cortex and inner medulla. Homogenous distribution of non-NMDA GluR2/3, sparse kainate KA1, and undetectable group I of metabotropic glutamate receptor were noted in the control kidneys. Ischemia-reperfusion kidneys showed enhanced renal NR1, but not NR2C and GluR2/3 expression, and were associated with decreased GFR/RBF and natriuretic/diuretic responses. Intrarenal NMDA agonists significantly reduced GFR, UV, U(Na)V, and U(K)V 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 restoring decreased GFR, UV, and U(Na)V levels. Ischemia-reperfusion upregulates renal NMDA NR1 receptor expression, leading to reduced glomerular and tubular function in the kidneys. The NMDA antagonist can ameliorate ischemia-reperfusion-induced renal dysfunction.
Yang
Chih-Ching
CC
Dept. of Physiology, College of Medicine, National Taiwan Univ., No. 1, Section 1, Jen-Ai Rd., Taipei, Taiwan.
Chien
Chiang-Ting
CT
Wu
Ming-Hsiou
MH
Ma
Ming-Chieh
MC
Chen
Chau-Fong
CF
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology*; D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C104723:glutamate receptor ionotropic, AMPA 3; D018698:Glutamic Acid; D015763:2-Amino-5-phosphonovalerate; C104722:glutamate receptor ionotropic, AMPA 2