期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 51, 期 10, 页码 1831-1841出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2011.08.014
关键词
Androgens; Angiotensin II; 20-HETE; Hypertension; Oxidative stress; Kidney; Kidney androgen-regulated protein; Sympathetic system; Free radicals
资金
- Ministerio de Educacion y Ciencia [SAF2005-05167, SAF 2007-63893]
- Instituto de Salud Carlos III [016/2006, FIS PI081351]
- Fundacion Matua Madrilefia and Senefro
- Fundacion Renal ifiigo Alvarez de Toledo
- Generalitat de Catalunya [2009SGR]
- Junta de Castilla y Leon [GR-100]
- European Regional Development Funds
Gender differences in the incidence and severity of hypertension have suggested the involvement of a sex-dependent mechanism. Transgenic (Tg) mice overexpressing kidney androgen-regulated protein (KAP) specifically in kidney showed hypertension associated with oxidative stress. Reactive oxygen species (ROS) are strongly implicated in the pathological signaling leading to hypertension in a framework that includes renin angiotensin system (RAS) activation, increased sympathetic activity, and cardiac remodeling. In this report. we observed that plasma levels of angiotensin II and catecholamines were increased in KAP Tg mice, compared with wild-type animals. Systemic administration of Tempol, a membrane-permeative superoxide dismutase mimetic, reduced arterial pressure as well as urinary excretion of oxidative stress markers and reduced both angiotensin II and norepinephrine plasma levels in MAP Tg mice. Intracerebroventricular administration of Tempol also reduced arterial pressure in Tg mice. Moreover, administration of apocynin and DPI, inhibitors of NADPH oxidase, a major source of ROS, also reduced arterial pressure and both angiotensin II and norepinephrine plasma levels in Tg mice. Thus, we analyzed the involvement of the RAS and sympathetic nervous system in MP Tg mouse hypertension. Both captopril and losartan reduced arterial blood pressure in Tg mice, as also occurred after beta-adrenergic blockade with atendol. Also, intracerebroventricular losartan administration reduced arterial pressure in KAP Tg mice. Our data demonstrate that hypertension in male KAP Tg mice is based on increased oxidative stress, increased sympathetic activity, and RAS activation. Moreover, our results suggest a role for increased oxidative stress in the CNS as a major cause of hypertension in these animals. (C) 2011 Elsevier Inc. All rights reserved.
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