Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells.
Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells.
复制标题
血管紧张素 II 2 型受体抑制大鼠肾近曲小管细胞中胰岛素受体的表达和功能。
DOI：
10.1016/j.jash.2017.11.009
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Zeng C
中科院分区：
文献类型：
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作者：
Yang Y;Chen C;Fu C;Xu Z;Lan C;Zeng Y;Chen Z;Jose PA;Zhang Y;Zeng C
肾素-血管紧张素系统和胰岛素都参与肾脏相关的血压调节。激活血管紧张素II型2受体（AT2R）可减少肾近端小管（RPT）细胞的钠重吸收，而胰岛素则产生相反的作用。我们推测AT2R对RPT细胞中的胰岛素受体表达有抑制作用，这可能影响肾脏钠转运，因此具有生理或病理意义。本研究发现，在Wistar-Kyoto （WKY）大鼠RPT细胞中，AT2R的激活以浓度和时间依赖性的方式抑制胰岛素受体的表达。在蛋白激酶C （PKC）抑制剂（PKC抑制剂肽19 - 31,10−6 mol/L）或磷脂酰肌醇3激酶抑制剂（wortmannin, 10−6 mol/L）存在的情况下，AT2R对胰岛素受体的抑制作用被阻断，表明PKC和磷脂酰肌醇3激酶都参与了信号通路。用激光共聚焦显微镜和免疫共沉淀法测定了AT2R与胰岛素受体之间的连锁关系。然而，AT2R激活对自发性高血压大鼠RPT细胞中胰岛素受体表达的影响是不同的。与WKY RPT细胞的作用相反，AT2R刺激增加了SHR RPT细胞的胰岛素受体。胰岛素（10−7 mol/L， 15分钟）增强了WKY和SHR RPT细胞Na+-K+- atp酶活性。CGP42112预处理可降低胰岛素对WKY RPT细胞Na+-K+- atp酶活性的刺激作用，而CGP42112预处理可提高SHR RPT细胞Na+-K+- atp酶活性。提示AT2R的激活可抑制RPT细胞中胰岛素受体的表达和功能。AT2R对胰岛素受体表达抑制作用的丧失可能与高血压的病理生理有关。
Both renin–angiotensin systems and insulin participate in kidney-involved blood pressure regulation. Activation of angiotensin II type 2 receptor (AT2R) decreases sodium reabsorption in renal proximal tubule (RPT) cells, whereas insulin produces the opposite effect. We presume that AT2R has an inhibitory effect on insulin receptor expression in RPT cells, which may affect renal sodium transport and therefore be of physiological or pathological significance. Our present study found that activation of AT2R inhibited insulin receptor expression in a concentration and time-dependent manner in RPT cells from Wistar-Kyoto (WKY) rats. In the presence of a protein kinase C (PKC) inhibitor (PKC inhibitor peptide 19–31, 10−6 mol/L) or a phosphatidylinositol 3 kinase inhibitor (wortmannin, 10−6 mol/L), the inhibitory effect of AT2R on insulin receptor was blocked, indicating that both PKC and phosphatidylinositol 3 kinase were involved in the signaling pathway. There was a linkage between AT2R and insulin receptor which was determined by both laser confocal microscopy and coimmunoprecipitation. However, the effect of AT2R activation on insulin receptor expression was different in RPT cells from spontaneously hypertensive rats (SHRs). Being contrary to the effect in WKY RPT cells, AT2R stimulation increased insulin receptor in SHR RPT cells. Insulin (10−7 mol/L, 15 minutes) enhanced Na+-K+-ATPase activity in both WKY and SHR RPT cells. Pretreatment with CGP42112 decreased the stimulatory effect of insulin on Na+-K+-ATPase activity in WKY RPT cells, whereas pretreatment with CGP42112 increased it in SHR RPT cells. It is suggested that activation of AT2R inhibits insulin receptor expression and function in RPT cells. The lost inhibitory effect of AT2R on insulin receptor expression may contribute to the pathophysiology of hypertension.