Angiotensin II inhibits activity of human organic anion transporter 3 through activation of protein kinase C alpha: Accelerating endocytosis of the transporter

作者：Duan Peng; Li Shanshan; You Guofeng^*

来源：European Journal of Pharmacology, 2010, 627(1-3): 49-55.

DOI：10.1016/j.ejphar.2009.10.048

• Drug transporter
• Regulation
• Angiotensin II
• Protein Kinase C
• Endocytosis
• COS-7 Cells

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.

• 出版日期2010-2-10