Reduced NO production rapidly aggravates renal function through the NF-κB/ET-1/ETA receptor pathway in DOCA-salt-induced hypertensive rats

[摘要] Aims: It has been reported that endothelin-1(ET-1) overproduction and reduced nitric oxide (NO) production are closely related to the progression of renal diseases. In the present study, we examined the interrelation between ET-1 and NO system using rats treated with the combination of deoxycorticosterone acetate (DOCA)-salt and a non selective NO synthase inhibitor N-omega-nitro-L-arginine (NOARG). Main methods: Rats were treated with DOCA-salt (15 mg/kg, plus drinking water containing 1% NaCl) for two weeks, and then additional treatment of NOARG (0.6 mg/ml in the drinking water) was performed for three days. Key findings: Combined treatment of DOCA-salt and NOARG drastically developed the severe renal dysfunction and tissue injury. This treatment additionally enhanced renal ET-1 production compared to the rats treated with DOCA-salt alone, whereas a selective ETA receptor antagonist ABT-627 completely prevented renal dysfunction and tissue injury. On the other hand, combined treatment of DOCA-salt and NOARG induced the phosphorylation of inhibitory protein kappa B (I kappa B), followed by the activation of nuclear factor-kappa B (NF-kappa B) in the kidney. In addition, pyrrolidine-dithiocarbamate completely suppressed not only NF-kappa B activation but also renal dysfunction and ET-1 overproduction. Significance: These results suggest that NF-kappa B/ET-1/ETA receptor-mediated actions are responsible for the increased susceptibility to DOCA-salt induced renal injuries in the case of reduced NO production. (c) 2012 Elsevier Inc. All rights reserved.

[发布日期] 2012-10-15

[效力级别]  Proceedings Paper

[关键词] DOCA-salt;Endothelin-1;ETA receptor;Nitric oxide;NF-kappa B