Altered NMDA receptor expression in renal toxicity: Protection with a receptor antagonist.
BACKGROUND
The N-methyl-d-aspartate (NMDA) receptor is expressed in the kidney. The receptor plays a major role in gentamicin ototoxicity. We assessed the role of the renal NMDA receptor subunits NR1 and NR2C in a model of gentamicin nephrotoxicity.


METHODS
Rats were exposed to either saline (control), high-dose, short-term gentamicin, or short-term gentamicin plus the NMDA antagonist MK-801 (short-term gentamicin + MK-801) for 3 days.


RESULTS
Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed that NR1 mRNA expression was significantly higher (P= 0.03) in the renal cortex of short-term gentamicin rats. NR2C subunit mRNA expression was unaltered in short-term gentamicin rats. Western blot analysis revealed that NR1 (P= 0.009) and NR2C (P= 0.003) protein abundance was significantly higher in the renal cortex short-term gentamicin rats. We assessed two potential intracellular pathways that may mediate short-term gentamicin/NMDA. Calpain I and II expression was similar in short-term gentamicin and control rats. Endothelin type B receptor (ETBR) expression was significantly increased in the renal cortex of short-term gentamicin rats (P= 0.0003), and urinary nitrite concentration (reflecting nitric oxide) was significantly increased in short-term gentamicin rats (P= 0.03). Serum creatinine was significantly elevated in short-term gentamicin animals (P= 0.03), and this increase was attenuated in short-term gentamicin + MK-801 rats. Blood pressure was higher in short-term gentamicin rats; this was attenuated in short-term gentamicin + MK-801 rats. Urine pH was significantly lower in short-term gentamicin (P < 0.0001) rats; this was reversed in short-term gentamicin + MK-801 (P= 0.005) rats. Urinary nitrite was significantly higher in short-term gentamicin rats; this was normalized in short-term gentamicin + MK-801 rats. MK-801 alone had no effect on clinical parameters.


CONCLUSIONS
NMDA receptor subunit expression is increased in short-term gentamicin animals, and the receptor likely mediates cell damage via the endothelin-ETBR-nitric oxide pathway. NMDA antagonism ameliorated renal damage after exposure to short-term gentamicin.
Leung
Jocelyn C
JC
Department of Pediatrics, Division of Neonatology and Division of Nephrology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Marphis
Tara
T
Craver
Randall D
RD
Silverstein
Douglas M
DM
D000818:Animals; D000900:Anti-Bacterial Agents / Q000506:poisoning*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005839:Gentamicins / Q000506:poisoning*; D007425:Intracellular Membranes / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control* / Q000652:urine; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009573:Nitrites / Q000652:urine; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005839:Gentamicins; D009573:Nitrites; D020033:Protein Isoforms; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate