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1 Department of Physiology, Mahidol University, Bangkok, Bangkok, Thailand
2 Department of Physiology, University of Arizona, Tucson, Arizona, USA
* To whom correspondence should be addressed. E-mail: shwright{at}u.arizona.edu.
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. Phorbol 12-myristate 13-acetate (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 
1-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 mitogen-activated protein kinase (MAPK).
Exposure to prostaglandin E2 (PGE2) or dibutyryl cyclic AMP (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 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 PE 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.
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