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.