title: Inhibitory effects of a dihydropyridine calcium channel blocker on renal injury in aldosterone-infused rats.
abstract: OBJECTIVE
  Recent in-vitro studies demonstrated that dihydropyridine calcium channel blockers have direct mineralocorticoid receptor antagonistic activity. The present study was conducted to examine the effects of a dihydropyridine calcium channel blocker, azelnidipine, on aldosterone-induced oxidative stress and renal injury.
  
  
  RESULTS
  Uninephrectomized rats subjected to 6 weeks treatment with aldosterone (0.75 microg/h, subcutaneous) and 1% NaCl (in drinking water) showed higher systolic blood pressure (SBP), urinary excretion of protein (UproteinV), glomerular cell proliferation and renal interstitial fibrosis than vehicle (2% ethanol)-infused rats. Aldosterone-induced renal injury was associated with increased renal cortical content of thiobarbituric acid-reactive substances (TBARS), NAD(P)H oxidase complex formation and mRNA expression of NAD(P)H oxidase membrane components (p22 and gp91). Administration of azelnidipine [3 mg/kg per day, orally (p.o.)] markedly attenuated the aldosterone-induced increases in SBP, UproteinV, renal cortical tissues TBARS content, NAD(P)H oxidase complex formation, mRNA levels of p22 and gp91, and morphological changes. In aldosterone-infused rats, treatment with a nonspecific vasodilator, hydralazine (5 mg/kg per day in drinking water) resulted in a reduction in SBP similar to azelnidipine; however, it did not affect any renal parameters. Treatment with azelnidipine suppressed aldosterone/mineralocorticoid receptor-dependent but not mineralocorticoid receptor-independent superoxide production in cultured rat mesangial cells.
  
  
  CONCLUSIONS
  These data suggest that dihydropyridine calcium channel blockers may elicit marked amelioration of aldosterone-induced renal injury through their inhibitory effects on NAD(P)H oxidase-dependent oxidative stress.
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University, Japan.
authors.forename: Yu-Yan
authors.initials: YY
authors.lastname: Fan
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nagai
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fujisawa
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Lu
authors.forename: Hua
authors.initials: H
authors.lastname: Fu
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.forename: Koji
authors.initials: K
authors.lastname: Ohmori
authors.forename: Naohisa
authors.initials: N
authors.lastname: Hosomi
authors.forename: Shoji
authors.initials: S
authors.lastname: Kimura
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Kiyomoto
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
mesh_terms: D000450:Aldosterone; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D024141:Collagen Type IV / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D003404:Creatinine / Q000097:blood / Q000652:urine; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use*; D004996:Ethidium / Q000031:analogs & derivatives; D015870:Gene Expression; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011507:Proteinuria / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C526316:CCN2 protein, rat; D002121:Calcium Channel Blockers; D024141:Collagen Type IV; D004095:Dihydropyridines; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D016212:Transforming Growth Factor beta; C067883:dihydroethidium; D055513:Connective Tissue Growth Factor; D000450:Aldosterone; D001383:Azetidinecarboxylic Acid; D003404:Creatinine; D019255:NADPH Oxidases; D004996:Ethidium; C061679:azelnidipine