title: Reduced NO production rapidly aggravates renal function through the NF-κB/ET-1/ETA receptor pathway in DOCA-salt-induced hypertensive rats.
abstract: OBJECTIVE
  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(ω)-nitro-L-arginine (NOARG).
  
  
  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.
  
  
  RESULTS
  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 ET(A) 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 (IκB), followed by the activation of nuclear factor-kappa B (NF-κB) in the kidney. In addition, pyrrolidine-dithiocarbamate completely suppressed not only NF-κB activation but also renal dysfunction and ET-1 overproduction.
  
  
  CONCLUSIONS
  These results suggest that NF-κB/ET-1/ET(A) receptor-mediated actions are responsible for the increased susceptibility to DOCA-salt induced renal injuries in the case of reduced NO production.
authors.affiliation: Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, Japan.
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Kimura
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ohkita
authors.forename: Maki
authors.initials: M
authors.lastname: Koyama
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D000077868:Atrasentan; D003900:Desoxycorticosterone / Q000633:toxicity; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D019332:Endothelin-1 / Q000378:metabolism*; D006973:Hypertension / Q000150:complications / Q000503:physiopathology*; D007674:Kidney Diseases / Q000209:etiology / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*; D012720:Severity of Illness Index; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D013859:Thiocarbamates / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D016328:NF-kappa B; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D017673:Sodium Chloride, Dietary; D013859:Thiocarbamates; D019335:Nitroarginine; C020972:pyrrolidine dithiocarbamic acid; D009569:Nitric Oxide; D003900:Desoxycorticosterone; D000077868:Atrasentan