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

David S. Miller, Caroline R. Sussman, J. Larry Renfro

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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)-2methylpiperazine (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 telcost 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.

Original languageEnglish (US)
Pages (from-to)F785-F795
JournalAmerican Journal of Physiology - Renal Physiology
Volume275
Issue number5 44-5
StatePublished - Nov 1 1998

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Keywords

  • Confocal microscopy
  • Fluorescence microscopy
  • Killifish
  • Multidrug resistance transporter
  • Phorbol ester
  • Renal secretion
  • Staurosporine
  • Teleost fish
  • Winter flounder

ASJC Scopus subject areas

  • Physiology
  • Urology

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