In the present study, we investigated a gender difference of atherosclerotic changes induced in apoE – deficient (ApoEKO)mice, focusing on oxidative stress, and the possible interaction between olmesartan, an AT₁ (angiotensin type 1 receptor)blocker(ARB), and estrogen. After treatment with high cholesterol diet(HCD) for 6 weeks, apparent atherosclerotic lesion formation including lipid deposition and increase in superoxide production and p47^phox expression were observed in ApoEKO mice. These changes were significantly greater in male than in female mice, although plasma cholesterol level was not different. Preceding ovariectomy enhanced atherosclerotic lesion and oxidative stress 6 weeks after HCD. The changes in ovariectomized mice were reversed by 17β-estradiol(80μg/kg/day)replacement. On the other hand, olmesartan(3 mg/kg/day)inhibited both atherosclerosis and oxidative stress observed in ApoEKO mice treated with HCD. The inhibitory effect of olmesartan on atherosclerosis was significantly stronger in female than in male and ovariectomized ApoEKO mice. Neither the smaller dose of estrogen(20μg/kg/day)nor olmesartan(0.5 mg/kg/day)influenced atherosclerosis and oxidative stress. However, co-administration of olmesartan and estrogen at these smaller doses attenuated atherosclerosis as well as oxidative stress. We further investigated interaction between AT₁ receptor stimulation and estrogen on NADPH oxidase activity using cultured VSMC, which mainly was expressed AT1 receptor. The NADPH oxidase activity in cultured VSMC was increased by Angiotensin II. 17β- estradiol attenuated NADPH oxidase activity induced by angiotensin II without affecting the expression of AT₁ receptor. These results indicate that estrogen enhances the inhibitory effect of AT₁ receptor blocker on atherosclerosis. Our results also suggest that estrogen and ARB act synergistically to inhibit oxidative stress, by attenuating NADPH oxidase activity.

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　Tubulointerstitial fibrosis (TIF) is considered a valid marker of progression of diabetic and non-diabetic nephropathy, that correlates negatively with creatinine clearance (CCr), and functional outcome. Since a number of clinical trails have revealed that angiotensin converting enzyme inhibitors (ACEi) slowed the rate of decline of renal function in proteinuric patients, it is suggested that ACEi can directly and/or indirectly affect TIF. Therefore, to test this hypothesis, we performed a prospective study for 3 years focusing on the effects of ACEi on functional outcome of patients with IgA nephropathy (IgAN) in relation to the degree of TIF. In the control group treated with amlodipine, the degree of TIF was negatively correlated with the reduction rate of CCr (dCCr), which was consistent with previous observation. By contrast, in the group treated with ACEi, the dCCr index was attenuated compared with the controls, and there was no correlation between the degree of TIF and the dCCr index. The latter suggested that ACEi had independent effects on renal fibrogenesis. Subsequently, we performed in vitro experiments to test whether angiotensinⅡ(AngⅡ) and aldosterone (ALD) had direct profibrotic effects on cultured human renal fibroblasts. Human renal fibroblasts expressed AngⅡ type1 receptor (AT1R) in vivo and in vitro. AngⅡ stimulated fibroblast proliferation, and typeⅠcollagen production of human renal fibroblasts via AT1R, especially in fibroblasts derived from a fibrosing kidney; this effect was partially mediated by secreted TGF-β. ALD could also promote proliferation of fibrosis-derived fibroblasts. In conclusion, ACEi can efficaciously retard the progression of IgAN with and without TIF equally, which is supposed to be partially due to its direct effects on renal fibrogenesis.

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