on February 7, 2005
Published online before print February 7, 2005, doi: 10.1161/01.HYP.0000154681.38944.9a
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Submitted on September 29, 2004
From the Department of Pharmacology (A.N., L.Y., Y.F., T.S., S.K., Y.A.), Research Equipment Center (Y.N.), and Second Department of Internal Medicine (H.K., M. Kohno), Kagawa Medical University, Japan; Department of Pharmacology (M. Kyaw, M.Y., T.T.), The University of Tokushima School of Medicine, Japan; Departments of Medical Engineering (N.K., F.K.) and Physiology (K.H., E.N., K.T.), Kawasaki Medical School, Kurashiki, Japan; and Department of Cardiovascular Physiology and Medical Engineering (F.K.), Okayama University Graduate School of Medicine and Dentistry, Japan. * To whom correspondence should be addressed. E-mail: akira{at}kms.ac.jp.
Abstract--We demonstrated recently that chronic administration of aldosterone to rats induces glomerular mesangial injury and activates mitogen-activated protein kinases including extracellular signal-regulated kinases 1/2 (ERK1/2). We also observed that the aldosterone-induced mesangial injury and ERK1/2 activation were prevented by treatment with a selective mineralocorticoid receptor (MR) antagonist, eplerenone, suggesting that the glomerular mesangium is a potential target for injuries induced by aldosterone via activation of MR. In the present study, we investigated whether MR is expressed in cultured rat mesangial cells (RMCs) and involved in aldosterone-induced RMC injury. MR expression and localization were evaluated by Western blotting analysis and fluorolabeling methods. Cell proliferation and micromechanical properties were determined by [3H]-thymidine uptake measurements and a nanoindentation technique using an atomic force microscope cantilever, respectively. ERK1/2 activity was measured by Western blotting analysis with an anti-phospho-ERK1/2 antibody. Protein expression and immunostaining revealed that MR was abundant in the cytoplasm of RMCs. Aldosterone (1 to 100 nmol/L) dose-dependently activated ERK1/2 in RMCs with a peak at 10 minutes. Pretreatment with eplerenone (10 µmol/L) significantly attenuated aldosterone-induced ERK1/2 phosphorylation. Aldosterone (100 nmol/L) treatment for 30 hours increased [3H]-thymidine incorporation and decreased the elastic modulus, indicating cellular proliferative and deforming effects of aldosterone, respectively. These aldosterone-induced changes in cellular characteristics were prevented by pretreatment with eplerenone or an ERK (MEK) inhibitor, PD988059 (100 µmol/L). The results indicate that aldosterone directly induces RMC proliferation and deformability through MR and ERK1/2 activation, which may contribute to the pathogenesis of glomerular mesangial injury.
Revised on November 5, 2004
Involvement of Aldosterone and Mineralocorticoid Receptors in Rat Mesangial Cell Proliferation and Deformability
Akira Nishiyama*;
Key words: mineralocorticoids • aldosterone
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