on August 8, 2005
Published online before print August 8, 2005, doi: 10.1161/01.HYP.0000174593.88899.68
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Submitted on April 28, 2005
From Research Equipment Center (Y.N., A.M.), RI Research Center (K.M.), Second Department of Internal Medicine (G.-P.S., M.R., H.K., M.K.), and Department of Pharmacology (M.R., S.K., Y.A., A.N.), Kagawa Medical University, Kagawa, Japan; Department of Pharmacology (M.Y.), Nara Medical University School of Medicine, Nara, Japan. * To whom correspondence should be addressed. E-mail: akira{at}kms.ac.jp.
Abstract--Recently, we demonstrated that in rats treated chronically with aldosterone and salt, severe tubulointerstitial fibrosis is associated with the activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERK1/2). Here, we investigated whether aldosterone stimulates collagen synthesis via ERK1/2-dependent pathways in cultured rat renal fibroblasts. Gene expression of mineralocorticoid receptor (MR) and types I, II, III, and IV collagen was measured by real-time polymerase chain reaction (PCR). MR protein expression and ERK1/2 activity were evaluated by Western blotting analysis with anti-MR and anti-phospho-ERK1/2 antibodies, respectively. Collagen synthesis was determined by [3H]-proline incorporation. Significant levels of MR mRNA and protein expression were observed in rat renal fibroblasts. Treatment with aldosterone (0.1 to 10 nmol/L) increased ERK1/2 phosphorylation in a concentration-dependent manner with a peak at 5 minutes. Aldosterone (10 nmol/L) also increased the mRNA levels of types I, III, and IV collagen at 36 hours but had no effect on the type II collagen mRNA level. [3H]-proline incorporation was significantly increased by aldosterone in both the medium and cell layer at 48 hours. Aldosterone-induced ERK1/2 phosphorylation was markedly attenuated by pretreatment with eplerenone (10 µmol/L), a selective MR antagonist, or PD98059 (10 µmol/L), a specific inhibitor of MAPK kinase/ERK kinase, which is the upstream activator of ERK1/2. In addition, both eplerenone and PD98059 prevented the aldosterone-induced increases in types I, III, and IV collagen mRNA and [3H]-proline incorporation. These results suggest that aldosterone stimulates collagen gene expression and synthesis via MR-mediated ERK1/2 activation in renal fibroblasts, which may contribute to the progression of aldosterone-induced tubulointerstitial fibrosis.
Revised on May 17, 2005
Aldosterone Stimulates Collagen Gene Expression and Synthesis Via Activation of ERK1/2 in Rat Renal Fibroblasts
Yukiko Nagai;
Key words: aldosterone • collagen • fibroblasts • mineralocorticoids
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