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Am J Physiol Renal Physiol 275: F785-F795, 1998;
0363-6127/98 $5.00
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Vol. 275, Issue 5, F785-F795, November 1998

Protein kinase C regulation of p-glycoprotein-mediated xenobiotic secretion in renal proximal tubule

David S. Miller1, Caroline R. Sussman2, and J. Larry Renfro2

1 Intracellular Regulation Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; and 2 Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269

Fluorescence microscopy, fluorescent substrates [daunomycin and a fluorescent cyclosporin A (CSA) derivative] and digital image analysis were used to examine the role of protein kinase C (PKC) in the control of p-glycoprotein in killifish renal proximal tubules. PKC activators, phorbol ester (phorbol 12-myristate 13-acetate, PMA) and dioctylglycerol, reduced luminal drug accumulation, and protein kinase inhibitors, staurosporine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), increased luminal accumulation; a PMA analog that does not activate PKC was without effect. PMA effects were blocked by staurosporine. The increase in luminal fluorescence caused by staurosporine was blocked by the p-glycoprotein substrate, CSA, indicating that this component of transport was indeed mediated by p-glycoprotein. Neither PMA, dioctylglycerol, nor protein kinase inhibitors altered cellular drug accumulation. Finally, in primary cultures of flounder proximal tubule cells, PMA decreased transepithelial [3H]daunomycin secretion. This pharmacological approach demonstrates that in teleost renal proximal tubule, p-glycoprotein-mediated xenobiotic secretion is negatively correlated with changes in PKC activity, a finding that conflicts with results from studies using mammalian tumor cells that express p-glycoprotein.

confocal microscopy; fluorescence microscopy; killifish; multidrug resistance transporter; phorbol ester; renal secretion; staurosporine; teleost fish; winter flounder


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