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Angiotensin II Receptor Type 1-Mediated Vascular Oxidative Stress and Proinflammatory Gene Expression in Aldosterone-Induced Hypertension: The Possible Role of Local Renin-Angiotensin System

Department of Clinical and Molecular Endocrinology (Y.Hiro., T.Y., N.S., T.S., M.Sa., M.Sh., Y.Hira.), Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan; Department of Pharmacology (S.T.), Osaka Medical College, Osaka 569-8686, Japan; and Department of Hypertension and Cardiorenal Medicine (N.K.), Dokkyo University School of Medicine, Tochigi 321-0293, Japan

Address all correspondence and requests for reprints to: Takanobu Yoshimoto, M.D., Ph.D., Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: tyoshimoto.cme{at}tmd.ac.jp.

Recently, aldosterone has been shown to activate local renin-angiotensin system in vitro. To elucidate the potential role of local renin-angiotensin system in aldosterone-induced cardiovascular injury, we investigated the effects of selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL), angiotensin (Ang) II type 1 receptor antagonist candesartan (ARB), and superoxide dismutase mimetic tempol (TEM) on the development of hypertension, vascular injury, oxidative stress, and inflammatory-related gene expression in aldosterone-treated hypertensive rats. The increased systolic blood pressure and vascular inflammatory changes were attenuated by cotreatment either with EPL, ARB, or TEM. Aldosterone increased angiotensin-converting enzyme expression in the aortic tissue; its effects were blocked by EPL but not by ARB or TEM. Aldosterone also increased Ang II contents in the aortic tissue in the presence of low circulating Ang II concentrations. Aldosterone induced expression of various inflammatory-related genes, whose effects were abolished by EPL, whereas the inhibitory effects of ARB and TEM varied depending on the gene. Aldosterone caused greater accumulation of the oxidant stress marker 4-hydroxy-2-neonenal in the endothelium; its effect was abolished by EPL, ARB, or TEM. Aldosterone increased mRNA levels of reduced nicotinamide adenine dinucleotide phosphate oxidase components; their effect was abolished by EPL, whereas ARB and TEM decreased only the p47phox mRNA level but not that of p22phox or gp91phox. The present findings suggest that the Ang II-dependent pathway resulting from vascular angiotensin-converting enzyme up-regulation and Ang II-independent pathway are both involved in the underlying mechanisms resulting in the development of hypertension, vascular inflammation, and oxidative stress induced by aldosterone.

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