Journal
JOURNAL OF HYPERTENSION
Volume 28, Issue 3, Pages 536-542Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/HJH.0b013e3283346b62
Keywords
aldosterone; big mitogen-activated protein kinase 1; eplerenone; mesangial cells; mineralocorticoid receptor
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20590253]
- Kagawa University Project Research Fund
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [20590253] Funding Source: KAKEN
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We previously demonstrated that high glucose-induced cell proliferation in cultured rat mesangial cells (RMCs) is mediated through activation of big mitogen-activated protein kinase 1 (BMK1). We also found that, in aldosterone-treated rats, mesangial proliferation is associated with BMK1 activation and that these effects were prevented by treatment with a selective mineralocorticoid receptor antagonist, eplerenone. In this study, we investigated the contribution of mineralocorticoid receptors to high glucose-induced BMK1 activation and cell proliferation in RMCs. BMK1 phosphorylation was measured by western blot analysis. Cell proliferation was evaluated by [H-3]-thymidine incorporation. High glucose treatment (15.5 mmol/l) increased BMK1 phosphorylation in both the nucleus and cytosol of RMCs. High glucose-induced BMK1 phosphorylation was attenuated by pretreatment with eplerenone (10 mu mol/l), mineralocorticoid receptor small interfering RNA or PD98059 (100 mu mol/l), a specific inhibitor of extracellular signal-regulated kinase kinase (MEK). Likewise, high glucose-induced increases in [H-3]-thymidine incorporation were prevented by eplerenone or PD98059 and transfection of dominant-negative MEK5, which is the upstream regulator of BMK1. These results suggest that mineralocorticoid receptors are involved in high glucose-induced BMK1 phosphorylation and cell proliferation. The inhibitory actions of mineralocorticoid receptor antagonists may contribute to their preventive effects on diabetic nephropathy, which have been reported in recent clinical studies. J Hypertens 28:536-542 (c) 2010 Wolters Kluwer Health (c) Lippincott Williams & Wilkins.
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