Regulation of Megalin Expression in Cultured Proximal Tubule Cells by Angiotensin II Type 1A Receptor- and Insulin-Mediated Signaling Cross Talk
Regulation of Megalin Expression in Cultured Proximal Tubule Cells by Angiotensin II Type 1A Receptor- and Insulin-Mediated Signaling Cross Talk
复制标题
DOI：
10.1210/en.2008-0886
复制
发表时间：
2009-02-01
期刊：
影响因子：
4.8
通讯作者：
Saito, Akihiko
中科院分区：
文献类型：
--
作者：
Hosojima, Michihiro;Sato, Hiroyoshi;Saito, Akihiko
慢性肾病患者肾小球滤过蛋白（包括白蛋白）近端小管内吞功能受损可导致蛋白尿/白蛋白尿的发生。然而，调节近端肾小管功能的机制在很大程度上是未知的。本研究旨在探讨血管紧张素II 1A型受体（AT(1A)R）和胰岛素介导的信号通路在调节近端小管细胞（ptc）中多配体内吞受体meggalin表达中的作用。负鼠肾ptc来源的OK细胞稳定表达大鼠AT(1A)R，但缺乏内源性血管紧张素II受体（AT(1A)R-OK细胞），用于本研究。血管紧张素II处理细胞分别在3 h和24 h孵育时间点抑制meggalin mRNA和蛋白的表达。血管紧张素II处理后24小时，细胞对白蛋白和受体相关蛋白、巨噬肽的内吞配体的摄取和降解受到抑制。ERK抑制剂部分阻止了AT(1A) r介导的megalin表达下降。胰岛素与AT(1A) r介导的ERK激活和meggalin表达降低竞争。磷脂酰肌醇3-激酶（PI3K）是胰岛素信号的主要组成部分，其抑制剂也抑制meggalin的表达，并且血管紧张素II可以阻止胰岛素受体底物(IRS)/PI3K系统的激活。总的来说，AT(1A) r介导的ERK信号参与抑制OK细胞系中meggalin的表达，而胰岛素与这一途径竞争。相反，与血管紧张素II竞争的胰岛素- irs /PI3K信号倾向于刺激meggalin的表达。综上所述，在培养的ptc中，存在AT(1A)R-和胰岛素介导的竞争性信号串扰调节meggalin的表达。（内分泌学150:871 - 878,2009）
Impairment of proximal tubular endocytosis of glomerular-filtered proteins including albumin results in the development of proteinuria/albuminuria in patients with chronic kidney disease. However, the mechanisms regulating the proximal tubular function are largely unknown. This study aimed to investigate the role of angiotensin II type 1A receptor (AT(1A)R)- and insulin-mediated signaling pathways in regulating the expression of megalin, a multiligand endocytic receptor in proximal tubule cells (PTCs). Opossum kidney PTC-derived OK cells that stably express rat AT(1A)R but are deficient in endogenous angiotensin II receptors (AT(1A)R-OK cells) were used for this study. Treatment of the cells with angiotensin II suppressed mRNA and protein expression of megalin at 3- and 24-h incubation time points, respectively. Cellular uptake and degradation of albumin and receptor-associated protein, megalin's endocytic ligands were suppressed 24 h after angiotensin II treatment. The AT(1A)R-mediated decrease in megalin expression was partially prevented by ERK inhibitors. Insulin competed with the AT(1A)R-mediated ERK activation and decrease in megalin expression. Inhibitors of phosphatidylinositol 3- kinase (PI3K), a major component of insulin signaling, also suppressed megalin expression, and activation of the insulin receptor substrate (IRS)/PI3K system was prevented by angiotensin II. Collectively the AT(1A)R-mediated ERK signaling is involved in suppressing megalin expression in the OK cell line, and insulin competes with this pathway. Conversely, the insulin-IRS/PI3K signaling, with which angiotensin II competes, tends to stimulate megalin expression. In conclusion, there is AT(1A)R- and insulin-mediated competitive signaling cross talk to regulate megalin expression in cultured PTCs. (Endocrinology 150: 871 - 878, 2009)