Angiotensin II inhibits activity of human organic anion transporter 3 through activation of protein kinase Cα: Accelerating endocytosis of the transporter
Angiotensin II inhibits activity of human organic anion transporter 3 through activation of protein kinase Cα: Accelerating endocytosis of the transporter
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DOI：
10.1016/j.ejphar.2009.10.048
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发表时间：
2010-02-10
影响因子：
5
通讯作者：
You, Guofeng
中科院分区：
文献类型：
--
作者：
Duan, Peng;Li, Shanshan;You, Guofeng
人体有机阴离子转运蛋白3 （hoAT3）属于有机阴离子转运蛋白家族，在许多临床重要药物的机体配置中起关键作用。在肾脏中，hOAT3通过三级转运机制发挥作用，涉及另外两种膜蛋白Na/ k - atp酶和Na-二羧酸共转运蛋白。在本研究中，我们建立了稳定表达hOAT3的COS-7细胞，并检测了蛋白激酶C （PKC）和血管紧张素II对hOAT3的调控。PKC激活和血管紧张素II均抑制hOAT3转运活性。血管紧张素II诱导的hOAT3活性抑制可以通过staurosporine （PKC的一般抑制剂）和Go6976 （PKC α特异性抑制剂，5,6,7,13-四氢-13-甲基-5-氧- 12h -吲哚[2,3-a]吡咯[3,4-c]咔唑-12-丙腈）处理表达hOAT3的细胞来阻止。对hOAT3表达和转运动力学的检测表明，血管紧张素II诱导的hOAT3活性抑制主要是由于细胞表面表达的降低，动力学上反映为V-max的降低，而K-m没有显著变化。这种血管紧张素II诱导的细胞表面hOAT-3表达下降是由于hOAT3内吞作用增加所致。然而，在这种情况下，血管紧张素II诱导的Na/ k - atp酶的内吞作用没有发生。我们得出结论，血管紧张素II通过激活PKC α抑制hOAT3活性，从而加速hOAT3的内吞作用。(C) 2009年Elsevier B.V.出版
Human organic anion transporter 3 (hoAT3) belongs to a family of organic anion transporters that play critical roles in the body disposition of numerous clinically important drugs. In the kidney, hOAT3 functions through a tertiary transport mechanism involving two other membrane proteins Na/K-ATPase and Na-dicarboxylate cotransporter. In the current study, we established COS-7 cells stably expressing hOAT3 and examined the regulation of hOAT3 by protein kinase C (PKC) and angiotensin II. Both PKC activation and angiotensin II inhibited hOAT3 transport activity. Angiotensin II induced inhibition of hOAT3 activity could be prevented by treating hOAT3-expressing cells with staurosporine, a general inhibitor for PKC, and with Go6976 (5,6,7,13-Tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile), a PKC alpha-specific inhibitor. Examination of hOAT3 expression and transport kinetics revealed that angiotensin II induced inhibition of hOAT3 activity mainly resulted from a decreased cell surface expression kinetically reflected as a decreased V-max without a significant change in K-m. Such angiotensin II induced decrease in cell surface expression of hOAT-3 was caused by an increase in hOAT3 endocytosis. However, angiotensin II induced endocytosis of Na/K-ATPase did not occur under such condition. We concluded that angiotensin II inhibited hOAT3 activity through the activation of PKC alpha, which led to an acceleration of hOAT3 endocytosis. (C) 2009 Published by Elsevier B.V.