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Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular Opossum Kidney Cells: Prostaglandin E₂ Acts via Receptor-Mediated Activation of Protein Kinase A

Physiologisches Institut der Universität Würzburg, Würzburg, Germany

Correspondence to Dr. Christoph Sauvant, Physiologisches Institut, Universität Würzburg, Röntgenring 9, 97070 Würzburg, Germany. Phone: ++49-931-31-2724; Fax: ++49-931-31-2741; E-mail: christoph.sauvant{at}mail.uniwuerzburg.de

ABSTRACT. It was shown previously that EGF induces release of the important prostanoid prostaglandin E₂ (PGE₂) in proximal tubular opossum kidney (OK) cells and PGE₂ then stimulates initial basolateral uptake of organic anions (OA) dose dependently. PGE₂ is a receptor agonist and a known substrate for the basolateral exchanger mediating OA uptake (OAT1 and/or OAT3). This study investigated the mechanism of short-term PGE₂ action on initial basolateral OA uptake in OK cells. PGE₂ stimulation of OA uptake was abolished by selective inhibition of adenylate cyclase (by MDL-12, 330A) or protein kinase A (PKA; by H89). PGE₂ stimulation of OA uptake persisted after preloading the cells with glutarate and was still abolished by inhibition of PKA. Selective activation of adenylate cyclase by forskolin led to identical results. These data contradicted the hypothesis that PGE₂ action on OA uptake is due to its action as a counter ion. Therefore, we tested whether the PGE₂ receptors (EP1 to 4) are involved in stimulation of OA uptake in OK cells by PGE₂. Because of their intracellular signaling profile, EP1 and EP3 were not taken into account as possible receptors for mediation of PGE₂-induced OA uptake. With the use of selective agonists (11-deoxy PGE₁ and butaprost), EP4 was pharmacologically identified as the receptor responsible for PGE₂-mediated stimulation of OA uptake. By reverse transcription–PCR, cloning, and subsequent sequencing, a homologue fragment to EP4 was identified in OK cells. EGF-induced stimulation of basolateral organic anion uptake was abolished by inhibition of adenylate cyclase or PKA. This indicates that EGF action is mediated by generation of PGE₂. The following model is proposed: PGE₂ generated in the cells does not act as a counter ion but activates adenylate cyclase. This is mediated by a homologue of EP4 receptor. cAMP then activates PKA, which stimulates initial basolateral uptake of OA in OK cells by a not-yet-known mechanism. PGE₂ is an organic anion, a potential stimulator of organic anion excretion, and an important mediator of inflammation all at once. Thus, the mechanism presented here may contribute to a limitation of inflammatory events in the kidney cortex interstitium.

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