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This version published online on January 11, 2007
Endocrinology, doi:10.1210/en.2006-1157
A more recent version of this article appeared on April 1, 2007
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Submitted on August 22, 2006
Accepted on January 2, 2007

Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expressions in aldosterone-induced hypertension: the possible role of local renin-angiotensin system

Yuki Hirono, Takanobu Yoshimoto*, Noriko Suzuki, Toru Sugiyama, Maya Sakurada, Shinji Takai, Naohiko Kobayashi, Masayoshi Shichiri, and Yukio Hirata

Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519; Department of Pharmacology, Osaka Medical College, Osaka 569-8686; Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Tochigi 321-0293, Japan

* To whom correspondence should be addressed. E-mail: tyoshimoto.cme{at}tmd.ac.jp.

Recently, aldosterone has been shown to activate local renin-angiotensin system (RAS) in vitro. To elucidate the potential role of local RAS 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 expressions in aldosterone-treated hypertensive rats (Aldo-rats). The increased systolic blood pressure and vascular inflammatory changes were attenuated by co-treatment either with EPL, ARB, or TEM. Aldosterone increased angiotensin-converting enzyme (ACE) 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, while the inhibitory effects of ARB and TEM varied depending on the gene. Aldosterone caused greater accumulation of the oxidant stress marker 4-HNE in the endothelium; its effect was abolished either by EPL, ARB, or TEM. Aldosterone increased mRNA levels of NAD(P)H oxidase components; their effect was abolished by EPL, while ARB and TEM only decreased p47phox mRNA level but not that of p22phox or gp91phox. The present findings suggest that the Ang II-dependent pathway resulting from vascular ACE 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.
Key words: aldosterone • local renin-angiotensin system • angiotensin-converting enzyme • oxidative stress • vascular inflammation




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