Acute regulation of OAT3-mediated estrone sulfate transport in isolated rabbit renal proximal tubules

S. Soodvilai, V. Chatsudthipong, K. K. Evans, S. H. Wright, W. H. Dantzler

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

We investigated the regulation of organic anion transport driven by the organic anion transporter 3 (OAT3), a multispecific OAT localized at the basolateral membrane of the renal proximal tubule. PMA, a PKC activator, inhibited uptake of estrone sulfate (ES), a prototypic substrate for OAT3, in a dose- and time-dependent manner. This inhibition was reduced by 100 nM bisindoylmaleimide I (BIM), a specific PKC inhibitor. The α1- adrenergic receptor agonist phenylephrine also inhibited ES uptake, and this effect was reduced by BIM. These results suggest that PKC activation downregulates OAT3-mediated organic anion transport. In contrast, epidermal growth factor (EGF) increased ES uptake following activation of MAPK. Exposure to PGE2 or dibutyryl (db)-cAMP also enhanced ES uptake. Stimulation produced by PGE2 and db-cAMP was prevented by the PKA inhibitor H-89, indicating that this stimulation required PKA activation. In addition, inhibition of cyclooxygenase 1 (COX1) (but not COX2) inhibited ES uptake. Furthermore, the stimulatory effect of EGF was eliminated by inhibition of either COX1 or PKA. These data suggest that EGF stimulates ES uptake by a process in which MAPK activation results in increased PGE2 production that, in turn, activates PKA and subsequently stimulates ES uptake. Interestingly, EGF did not induce upregulation immediately following phenylephrine-induced downregulation; and phenylephrine did not induce downregulation immediately after EGF-induced upregulation. These data are the first to show the regulatory response of organic anion transport driven by OAT3 in intact renal proximal tubules.

Original languageEnglish (US)
Pages (from-to)F1021-F1029
JournalAmerican Journal of Physiology - Renal Physiology
Volume287
Issue number5 56-5
DOIs
StatePublished - Nov 2004

Keywords

  • Kidney
  • Mitogen-activating protein kinase
  • Organic anion
  • Protein kinase C
  • p-aminohippurate

ASJC Scopus subject areas

  • Physiology
  • Urology

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