TY - JOUR
T1 - Involvement of mineralocorticoid receptor in high glucose-induced big mitogen-activated protein kinase 1 activation and mesangial cell proliferation
AU - Liu, Gang
AU - Miyata, Kayoko
AU - Hitomi, Hirofumi
AU - Yao, Li
AU - Sun, Guang Ping
AU - Suzaki, Yuki
AU - Hosomi, Naohisa
AU - Kiyomoto, Hideyasu
AU - Nakano, Daisuke
AU - Tamaki, Toshiaki
AU - Yoshizumi, Masanori
AU - Nishiyama, Akira
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2010/3
Y1 - 2010/3
N2 - 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 [3H]-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 μmol/l), mineralocorticoid receptor small interfering RNA or PD98059 (100 μmol/l), a specific inhibitor of extracellular signal-regulated kinase kinase (MEK). Likewise, high glucose-induced increases in [3H]-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.
AB - 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 [3H]-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 μmol/l), mineralocorticoid receptor small interfering RNA or PD98059 (100 μmol/l), a specific inhibitor of extracellular signal-regulated kinase kinase (MEK). Likewise, high glucose-induced increases in [3H]-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.
KW - Aldosterone
KW - Big mitogen-activated protein kinase 1
KW - Eplerenone
KW - Mesangial cells
KW - Mineralocorticoid receptor
UR - http://www.scopus.com/inward/record.url?scp=77149130935&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77149130935&partnerID=8YFLogxK
U2 - 10.1097/HJH.0b013e3283346b62
DO - 10.1097/HJH.0b013e3283346b62
M3 - Article
C2 - 20090557
AN - SCOPUS:77149130935
VL - 28
SP - 536
EP - 542
JO - Journal of Hypertension
JF - Journal of Hypertension
SN - 0263-6352
IS - 3
ER -