Mineralocorticoid receptor activation: a major contributor to salt-induced renal injury and hypertension in young rats

Abstract

Kawarazaki H, Ando K, Fujita M, Matsui H, Nagae A, Muraoka K, Kawarasaki C, Fujita T. Mineralocorticoid receptor activation: a major contributor to salt-induced renal injury and hypertension in young rats. Am J Physiol Renal Physiol 300: F1402-F1409, 2011. First published April 6, 2011 doi:10.1152/ajprenal.00691.2010.-Excessive salt intake is known to preferentially increase blood pressure (BP) and promote kidney damage in young, salt-sensitive hypertensive human and animal models. We have suggested that mineralocorticoid receptor (MR) activation plays a major role in kidney injury in young rats. BP and urinary protein were compared in young (3-wk-old) and adult (10-wk-old) uninephrectomized (UNx) Sprague-Dawley rats fed a high (8.0%)-salt diet for 4 wk. The effects of the MR blocker eplerenone on BP and renal injury were examined in the high-salt diet-fed young UNx rats. Renal expression of renin-angiotensinaldosterone (RAA) system components and of inflammatory and oxidative stress markers was also measured. The effects of the angiotensin receptor blocker olmesartan with or without low-dose aldosterone infusion, the aldosterone synthase inhibitor FAD286, and the antioxidant tempol were also studied. Excessive salt intake induced greater hypertension and proteinuria in young rats than in adult rats. The kidneys of young salt-loaded rats showed marked histological injury, overexpression of RAA system components, and an increase in inflammatory and oxidative stress markers. These changes were markedly ameliorated by eplerenone treatment. Olmesartan also ameliorated salt-induced renal injury but failed to do so when combined with low-dose aldosterone infusion. FAD286 and tempol also markedly reduced urinary protein. UNx rats exposed to excessive salt at a young age showed severe hypertension and renal injury, likely primarily due to MR activation and secondarily due to angiotensin receptor activation, which may be mediated by inflammation and oxidative stress. salt sensitivity; aldosterone; oxidative stress; renin-angiotensin OBSERVATIONAL STUDIES HAVE suggested that increased blood pressure (BP) in childhood correlates with increased BP in adulthood (36). Hypertension is closely related to kidney dysfunction, which can cause increased BP. Therefore, both BP control and maintenance of kidney health at a young age may be critical for BP management later in life.Salt consumption among very young children has increased in developed countries at a faster rate than in developing countries (9,28,33). It is believed that high salt (HS) intake during prepuberty contributes to high BP later in life (1, 23). In addition, increased BP resulting from excessive salt consumption has been shown to be enhanced in the young in several animal models of salt-sensitive (SS) hypertension (35). We previously demonstrated that in Dahl SS rats, an SS hypertension model, HS intake at a young age accelerates the development of kidney injury and hypertension (12). Interestingly, salt restriction during infant weaning has been reported to lo...

Sympathoexcitation by Brain Oxidative Stress Mediates Arterial Pressure Elevation in Salt-Induced Chronic Kidney Disease

“…Moreover, to investigate the role of brain ROS, ICV administration of Tempol was continued for 4 weeks in the salt-loaded uninephrectomized rats. In this way, 6 different experimental groups were created: sham-operated rats raised with a normal (sham) or high-salt diet (shamϩHS), uninephrectomized rats raised with a normal (Unx) or high-salt diet (UnxϩHS), 29,30 moxonidine-treated UnxϩHS rats (UnxϩHSϩMox), and chronic ICV Tempol-treated UnxϩHS rats (UnxϩHSϩICV temp).…”

“…In the present study, to clarify our hypothesis, we examined the following points by using young, salt-loaded, uninephrectomized Sprague-Dawley rats 29,30 as a salt-induced CKD model. We evaluated the responses of renal sympathetic nerve activity (RSNA) and arterial pressure to acute intracerebroventricular (ICV) administration of an antioxidant agent, Tempol, and the level of ROS in the hypothalamus.…”

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“…For instance, it is likely that lower dietary salt intake decreases the deleterious effects of aldosterone. [29][30][31][32] The residual excess risk may be attributable to a direct effect of hyperaldosteronism on target organs or to unmeasured hemodynamic confounders, such as higher nighttime BP, although it has been reported that nighttime BP in patients with PA is not consistently higher than that in EH patients with similar daytime BP. 33,34 Cardiovascular complications were not significantly more frequent in PA patients with low plasma potassium, suggesting that the higher frequency of cardiovascular complications in PA patients did not result from an indirect effect mediated by plasma potassium.…”

Influence of Aldosterone and Salt or Ouabain in A10 Rat Aorta Smooth Muscle Cells

“…The interaction between salt and aldosterone concerning vessel function or possible remodeling gains rising importance. Up to now, the interplay between salt and aldosterone on vessel function has been studied predominantly in whole animals [3,4,5]. Other studies suggest that aldosterone can generate an inflammatory milieu with the formation of reactive oxygen species (ROS) and matrix proteins [6,7].…”