Altered NMDA receptor expression in renal toxicity: Protection with a receptor antagonist

Abstract

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. Conclusion. 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.