Terada Yoshio, Kobayashi Takahiko, Kuwana Hitoshi, Tanaka Hiroyuki, Inoshita Seiji, Kuwahara Michio, Sasaki Sei
Department of Nephrology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
J Am Soc Nephrol. 2005 Aug;16(8):2296-305. doi: 10.1681/ASN.2005020129. Epub 2005 Jun 23.
Recently, attention has been focused on the role of aldosterone in the pathophysiology of hypertension and cardiovascular disease. Several clinical and experimental data support the hypothesis that aldosterone contributes to the progression of renal injury. However, the molecular mechanisms of the effects of aldosterone in signal transduction and the cell-cycle progression of mesangial cells are not well known. For determining the signaling pathway of aldosterone in cultured mesangial cells, the effects of aldosterone on the mitogen-activated protein kinase 1/2 (MAPK1/2) pathway and the promoter activities of cyclin D1, cyclin A, and cyclin E were investigated. First, it was shown that the mineralocorticoid receptor (MR) was expressed in rat mesangial cells and glomeruli and that aldosterone stimulated the proliferation of mesangial cells via the MR and MAPK1/2 pathway. Next, it was demonstrated that aldosterone stimulated Ki-RasA, c-Raf kinase, MEK1/2, and MAPK1/2 in rat mesangial cells. Aldosterone induced cyclin D1 and cyclin A promoter activities and protein expressions, as well as the increments of CDK2 and CDK4 kinase activities. The presence of CYP11B2 and 11beta-HSD2 mRNA in rat mesangial cells also was shown. In conclusion, aldosterone seems to exert mainly MR-induced effects that stimulate c-Raf, MEK1/2, MAPK1/2, the activities of CDK2 and CDK4, and the cell-cycle progression in mesangial cells. MR antagonists may serve as a potential therapeutic approach to mesangial proliferative disease.
最近，醛固酮在高血压和心血管疾病病理生理学中的作用受到了关注。多项临床和实验数据支持醛固酮促进肾损伤进展这一假说。然而，醛固酮在信号转导以及系膜细胞细胞周期进程中的作用的分子机制尚不清楚。为了确定醛固酮在培养的系膜细胞中的信号通路，研究了醛固酮对丝裂原活化蛋白激酶1/2（MAPK1/2）通路以及细胞周期蛋白D1、细胞周期蛋白A和细胞周期蛋白E启动子活性的影响。首先，研究表明盐皮质激素受体（MR）在大鼠系膜细胞和肾小球中表达，且醛固酮通过MR和MAPK1/2通路刺激系膜细胞增殖。接下来，证实醛固酮刺激大鼠系膜细胞中的Ki-RasA、c-Raf激酶、MEK1/2和MAPK1/2。醛固酮诱导细胞周期蛋白D1和细胞周期蛋白A启动子活性及蛋白表达，以及CDK2和CDK4激酶活性增加。还显示大鼠系膜细胞中存在CYP11B2和11β-HSD2 mRNA。总之，醛固酮似乎主要发挥MR诱导的效应，刺激c-Raf、MEK1/2、MAPK1/2、CDK2和CDK4的活性以及系膜细胞的细胞周期进程。MR拮抗剂可能是治疗系膜增生性疾病的一种潜在方法。
