Published online before print September 17, 2007, doi: 10.1161/HYPERTENSIONAHA.107.091058
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(Hypertension. 2007;50:877.)
© 2007 American Heart Association, Inc.
Original Articles |
Salt-Induced Nephropathy in Obese Spontaneously Hypertensive Rats Via Paradoxical Activation of the Mineralocorticoid Receptor
Role of Oxidative Stress
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.
Correspondence to Miki Nagase, Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail mnagase-tky{at}umin.ac.jp
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-ß1 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 11ß-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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