The Imai rat is a model of spontaneous focal glomerulosclerosis, which leads to heavy proteinuria, hyperlipidemia, hypertension, and progressive renal failure. Treatment with AT1 blockers (ARBs) ameliorates proteinuria, hyperlipidemia, and nephropathy in this model. Progression of renal disease in 5/6 nephrectomized rats is associated with activation of the intrarenal angiotensin system, up-regulation of the oxidative, inflammatory, and fibrogenic pathways, and impaired activity of nuclear factor-erythroid-2-related factor 2 (Nrf2), the master regulator of genes encoding antioxidant molecules. We hypothesized that progressive nephropathy in the Imai rat is accompanied by oxidative stress, inflammation, and impaired Nrf2 activation and that amelioration of nephropathy with AT1 receptor blockade in this model may be associated with the reversal of these abnormalities. Ten-week-old Imai rats were randomized to the ARB-treated (olmesartan, 10 mg/kg/day for 24 weeks) or vehicle-treated groups. Sprague-Dawley rats served as controls. At 34 weeks of age Imai rats showed heavy proteinuria, hypoalbuminemia, hypertension, azotemia, glomerulosclerosis, tubulointerstitial inflammation, increased angiotensin II expressing cell population, up-regulations of AT1 receptor, AT2 receptor, NAD(P)H oxidase, and inflammatory mediators, activation of nuclear factor-κB and reduction of Nrf2 activity and expression of its downstream gene products in the renal cortex. ARB therapy prevented nephropathy, suppressed oxidative stress and inflammation, and restored Nrf2 activation and expression of the antioxidant enzymes. Thus progressive focal glomerulosclerosis in the Imai rats is associated with oxidative stress, inflammation, and impaired Nrf2 activation. These abnormalities are accompanied by activation of intrarenal angiotensin system and can be prevented by ARB administration.