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.
BACKGROUND: The N-methyl-d-aspartate (NMDA) receptor is expressed in the kidney. The receptor plays a major role in gentamicinototoxicity. We assessed the role of the renal NMDA receptor subunits NR1 and NR2C in a model of gentamicinnephrotoxicity. 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 gentamicinrats. NR2C subunit mRNA expression was unaltered in short-term gentamicinrats. 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 gentamicinrats. 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 gentamicinrats (P= 0.0003), and urinary nitrite concentration (reflecting nitric oxide) was significantly increased in short-term gentamicinrats (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-801rats. Blood pressure was higher in short-term gentamicinrats; this was attenuated in short-term gentamicin + MK-801rats. 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 gentamicinrats; this was normalized in short-term gentamicin + MK-801rats. 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.
Authors: Omar Cauli; Alba González-Usano; Andrea Cabrera-Pastor; Carla Gimenez-Garzó; Pilar López-Larrubia; Amparo Ruiz-Sauri; Vicente Hernández-Rabaza; Malgorzata Duszczyk; Michal Malek; Jerzy W Lazarewicz; Arturo Carratalá; Amparo Urios; Alfonso Miguel; Isidro Torregrosa; Carmen Carda; Carmina Montoliu; Vicente Felipo Journal: Neuromolecular Med Date: 2013-12-13 Impact factor: 3.843
Authors: Chun Zhang; Fan Yi; Min Xia; Krishna M Boini; Qing Zhu; Laura A Laperle; Justine M Abais; Christopher A Brimson; Pin-Lan Li Journal: Antioxid Redox Signal Date: 2010-10-01 Impact factor: 8.401
Authors: Jason A Funk; Michael G Janech; Joshua C Dillon; John J Bissler; Brian J Siroky; P Darwin Bell Journal: J Am Soc Nephrol Date: 2014-02-08 Impact factor: 10.121
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