Olmesartan ameliorates progressive glomerular injury in subtotal nephrectomized rats through suppression of superoxide production.
Angiotensin type 1 receptor blockers are more effective than other antihypertensive agents in slowing the progression of renal disease. Angiotensin II (Ang II) induces production of NAD(P)H oxidase-dependent superoxide in vascular and mesangial cells, but the direct role of Ang II in glomerular superoxide production remains unknown. Here we examined the effect of Ang II on superoxide production both ex vivo and in vivo. Ang II increased superoxide generation in isolated normal glomeruli in a dose-dependent manner, and co-incubation with olmesartan, an angiotensin type 1 receptor blocker, suppressed such increase. Subtotal nephrectomized rats (Nx, n=8) showed impaired renal function, increased glomerular sclerosis, and significantly high superoxide production in glomeruli. These changes were inhibited in olmesartan-treated (n=8), but not hydralazine-treated (n=8) Nx rats. Oxidative stress and nitrosative stress were observed in Nx glomeruli, as evidenced by increased levels of carbonyl protein and nitrotyrosine formation, respectively. These changes were inhibited by 8-week treatment with olmesartan. The apoptosis observed in Nx glomeruli was also suppressed by olmesartan. Superoxide generation in Nx glomeruli was blocked by an NAD(P)H oxidase inhibitor, diphenylene iodinium. The mRNA expression levels of two NAD(P)H oxidase subunits were increased in Nx, and olmesartan significantly reduced the mRNA expression levels. These results indicate that Ang II directly induced superoxide production through activation of NAD(P)H oxidase, and olmesartan would inhibit superoxide production and oxidative stress independent of its blood pressure-lowering effect. These findings support the notion that superoxide plays a primary role in glomerular injury in chronic kidney disease.
Fujimoto
Sohachi
S
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan.
Satoh
Minoru
M
Horike
Hideyuki
H
Hatta
Hidekazu
H
Haruna
Yoshisuke
Y
Kobayashi
Shinya
S
Namikoshi
Tamehachi
T
Arakawa
Sayaka
S
Tomita
Naruya
N
Kashihara
Naoki
N
D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics; D009392:Nephrectomy; D009569:Nitric Oxide / Q000502:physiology; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D012333:RNA, Messenger; D013777:Tetrazoles; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; C437965:olmesartan; D019255:NADPH Oxidases; C515768:Cyba protein, rat