Published Online
on September 17, 2007

A more recent version of this article appeared on November 1, 2007

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Submitted on March 23, 2007
Revised on April 11, 2007

Salt-Induced Nephropathy in Obese Spontaneously Hypertensive Rats Via Paradoxical Activation of the Mineralocorticoid Receptor. Role of Oxidative Stress

Miki Nagase^*; Hiromitsu Matsui; Shigeru Shibata; Takanari Gotoda; and Toshiro Fujita

From the Departments of Nephrology and Endocrinology (M.N., H.M., S.S., T.G., T.F.) and Clinical and Molecular Epidemiology, 22nd Century Medical and Research Center (M.N., T.G.), University of Tokyo Graduate School of Medicine, Japan.

^* To whom correspondence should be addressed. E-mail: mnagase-tky{at}umin.ac.jp.

Abstract—Aldosterone is implicated in the pathogenesis of proteinuria and chronic kidney disease. We previously demonstrated the contribution of elevated serum aldosterone in the early nephropathy of SHR/NDmcr-cp (SHR/cp), a rat model of metabolic syndrome. In the present study, we investigated the effect of salt loading on renal damage in SHR/cps and explored the underlying mechanisms. SHR/cps fed a high-sodium diet for 4 weeks developed severe hypertension, massive proteinuria, and advanced renal lesions. High salt also worsened glomerular podocyte impairment. Surprisingly, selective mineralocorticoid receptor (MR) antagonist eplerenone dramatically ameliorated the salt-induced proteinuria and renal injury in SHR/cps. Although salt loading reduced circulating aldosterone, it increased nuclear MR and expression of aldosterone effector kinase Sgk1 in the kidney. Gene expressions of transforming growth factor-1 and plasminogen activator inhibitor-1 were also enhanced in the kidneys of salt-loaded SHR/cps, and eplerenone completely inhibited these injury markers. To clarify the discrepancy between decreased aldosterone and enhanced MR signaling by salt, we further investigated the role of oxidative stress, a putative key factor mediating salt-induced tissue damage. Interestingly, antioxidant Tempol attenuated the salt-evoked MR upregulation and Sgk1 induction and alleviated proteinuria and renal histological abnormalities, suggesting the involvement of oxidative stress in salt-induced MR activation. MR activation by salt was not attributed to increased serum corticosterone or reduced 11-hydroxysteroid dehydrogenase type 2 activity. In conclusion, sodium loading exacerbated proteinuria and renal injury in metabolic syndrome rats. Salt reduced circulating aldosterone but caused renal MR activation at least partially via induction of oxidative stress, and eplerenone effectively improved the nephropathy.

Key words: aldosterone • mineralocorticoids • metabolic syndrome • sodium • dietary • oxidative stress (kidney) • chronic kidney disease • proteinuria • eplerenone

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John W. Funder
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