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

Abstract

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.

Redox Control of Renal Function and Hypertension

“…In addition, aldosterone itself has certain actions that are independent of Ang II stimulation. For example, aldosterone acts through AT 1 R to mediate vascular oxidative stress by increasing mRNA levels of reduced nicotinamide adenine dinucleotide phosphate oxidase components; this effect was abolished by selective MR antagonism, whereas AT 1 R blockade and tempol decreased only the p47 phox mRNA level but not that of p22 phox or gp91 phox (122). In the same study, MR antagonism uniformly abrogated aldosterone-mediated stimulation of proinflammatory genes, whereas AT 1 R blockade and tempol had gene-specific effects.…”

Aldosterone activates endothelial exocytosis

“…Furthermore, aldosterone increases oxidant stress, which in turn promotes vascular inflammation. In particular, aldosterone increases expression of the NADPH oxidase subunits p22phox and gp91phox in the aorta, leading to an increase in reactive oxygen species (28,29). Aldosterone also decreases endothelial expression of glucose-6-phosphate dehydrogenase (G6PD), leading to increased oxidant stress and decreased nitric oxide (NO) levels (30).…”

High-sodium intake aggravates myocardial injuries induced by aldosterone via oxidative stress in Sprague-Dawley rats

“…This postulated mechanism could well explain our study results, with high-sodium intake potentially aggravating myocardial injuries induced by aldosterone through up-regulated oxidative stress. The hypothesis has been supported by previous studies, which showed that the development of hypertension and the regression of cardiovascular remodeling were attenuated in mineralocorticoid treated animals after the treatment of antioxidant drugs, such as the superoxide dismutase mimetic Tempol [21,22] , the NADPH oxidase inhibitor apocynin [23,24] or N-acetylcysteine [5] . Increased oxidative stress might also trigger and deteriorate inflammation.…”