Open AccessRegulation of human organic anion transporter 1 by ANG II: involvement of protein kinase Cα
Author(s) -
Shanshan Li,
Peng Duan,
Guofeng You
Publication year - 2009
Publication title -
endocrinology and metabolism/american journal of physiology: endocrinology and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.507
H-Index - 201
eISSN - 1522-1555
pISSN - 0193-1849
DOI - 10.1152/ajpendo.90713.2008
Subject(s) - protein kinase c , organic anion transporter 1 , chemistry , transporter , gene isoform , pharmacology , cell , microbiology and biotechnology , biochemistry , signal transduction , biology , gene
Human organic anion transporter 1 (hOAT1) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti-tumor drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT1 is abundantly expressed in the kidney. In the current study, we examined the regulation of hOAT1 by ANG II in kidney COS-7 cells. ANG II induced a concentration- and time-dependent inhibition of hOAT1 transport activity. Such inhibition mainly resulted from a decreased cell surface expression without a change in total cell expression of the transporter, kinetically revealed as a decreased maximal velocity without significant change in Michaelis constant. ANG II-induced inhibition of hOAT1 activity could be prevented by treating hOAT1-expressing cells with staurosporine, a general protein kinase C (PKC) inhibitor. To obtain further information on which PKC isoform mediates ANG II regulation of hOAT1 activity, cellular distribution of various PKC isoforms was examined in cells treated with or without ANG II. We showed that ANG II treatment resulted in a significant translocation of PKCalpha from cytosol to membrane, and such translocation was blocked by treating hOAT1-expressing cells with Gö-6976, a PKCalpha-specific inhibitor. We further showed that ANG II-induced inhibition of hOAT1 activity and retrieval of hOAT1 from the cell surface could also be prevented by treating hOAT1-expressing cells with Gö-6976. We concluded that ANG II inhibited hOAT1 activity through activation of PKCalpha, which led to the redistribution of the transporter from the cell surface to the intracellular compartments.