title: Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability.
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 micromol/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 micromol/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.
authors.affiliation: Department of Pharmacology, Kagawa Medical University 1750-1 Ikenobe, Miki-cho, Kita-gun Kagawa 761-0793, Japan. akira@kms.ac.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Li
authors.initials: L
authors.lastname: Yao
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Fan
authors.forename: Moe
authors.initials: M
authors.lastname: Kyaw
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kataoka
authors.forename: Ken
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nagai
authors.forename: Emi
authors.initials: E
authors.lastname: Nakamura
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: Takatomi
authors.initials: T
authors.lastname: Shokoji
authors.forename: Shoji
authors.initials: S
authors.lastname: Kimura
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Kiyomoto
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tsujioka
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kajiya
authors.forename: Youichi
authors.initials: Y
authors.lastname: Abe
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D005920:Glomerular Mesangium / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism / Q000502:physiology*
chemical_list: D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3