Involvement of mineralocorticoid receptor in high glucose-induced big mitogen-activated protein kinase 1 activation and mesangial cell proliferation
Involvement of mineralocorticoid receptor in high glucose-induced big mitogen-activated protein kinase 1 activation and mesangial cell proliferation
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DOI：
10.1097/hjh.0b013e3283346b62
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发表时间：
2010-03-01
影响因子：
4.9
通讯作者：
Nishiyama, Akira
中科院分区：
文献类型：
--
作者：
Liu, Gang;Miyata, Kayoko;Nishiyama, Akira
我们之前已经证明，高糖诱导的培养大鼠系膜细胞（RMCs）的细胞增殖是通过大丝裂原活化蛋白激酶1 （BMK1）的激活介导的。我们还发现，在醛固酮治疗的大鼠中，系膜增殖与BMK1激活有关，而这些影响可以通过选择性矿皮质激素受体拮抗剂epleenone治疗来阻止。在这项研究中，我们研究了矿化皮质激素受体在高糖诱导的RMCs中BMK1激活和细胞增殖中的作用。western blot检测BMK1磷酸化水平。用[H-3]-胸苷结合法评价细胞增殖。高葡萄糖处理（15.5 mmol/l）增加了RMCs细胞核和细胞质中BMK1的磷酸化。用eplerenone （10 μ mol/l）、矿皮质激素受体小干扰RNA或细胞外信号调节激酶（MEK）特异性抑制剂PD98059 （100 μ mol/l）预处理可减弱高糖诱导的BMK1磷酸化。同样，高糖诱导的[H-3]-胸苷结合的增加可以通过epleenone或PD98059和转染优势阴性的MEK5 （BMK1的上游调节因子）来阻止。这些结果表明，矿化皮质激素受体参与高糖诱导的BMK1磷酸化和细胞增殖。矿皮质激素受体拮抗剂的抑制作用可能有助于其对糖尿病肾病的预防作用，这在最近的临床研究中已被报道。[J]中华医学杂志，2010,28 (3):536-542 (c)。
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.