Angiotensin II (Ang II) and reactive oxidative species (ROS) that are produced by
NADPH oxidase have been implicated in the progression of
glomerulonephritis (GN). This study examined the effect of simultaneously interrupting Ang II and ROS with an Ang II receptor blocker (ARB),
candesartan, and a
free radical scavenger,
probucol, in a model of progressive mesangioproliferative GN induced by the injection of
anti-Thy-1 antibody into uninephrectomized rats. Nephritic rats were divided into four groups and given daily oral doses of the following: Vehicle, 1%
probucol diet, 70 mg/L
candesartan in
drinking water, and
probucol plus
candesartan. These treatments lasted until day 56. Vehicle-treated nephritic rats developed progressively elevated
proteinuria and glomerulosclerosis.
Candesartan kept
proteinuria significantly lower than vehicle or
probucol. The addition of
probucol to
candesartan normalized urinary
protein excretion. Increases in BP in nephritic rats were lowered by these treatments, except with
probucol. It is interesting that both glomerular cell number and glomerulosclerosis were significantly decreased by
candesartan and normalized by the addition of
probucol. Immunohistochemical studies for
TGF-beta1,
collagen type I, and
fibronectin revealed that the combined treatment abolished glomerular fibrotic findings compared with
candesartan. In addition, glomerular expression of
NADPH oxidase components and
superoxide production suggested that the combined treatment completely eliminated
NADPH oxidase-associated ROS production. In conclusion, our study provides the first evidence that the
antioxidant probucol, when added to an Ang II receptor blockade, fully arrests
proteinuria and
disease progression in GN. Furthermore, the data suggest that
NADPH oxidase-associated ROS production may play a pivotal role in the progression of GN. The combination of
probucol and
candesartan may represent a novel route of
therapy for patients with progressive GN.