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Prostaglandin E₂ Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

Physiologisches Institut, Universität Würzburg, Würzburg, Germany

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

Received for publication July 14, 2005. Accepted for publication October 11, 2005.

Prostaglandin E₂ (PGE₂) is the principal mediator of fever and inflammation. Recently, evidence emerged that during febrile response, PGE₂ that is generated in the periphery enters the hypothalamus and contributes to the maintenance of fever. In a rat model of fever generation, peripheral PGE₂ is increased, whereas clearance by metabolism of peripheral PGE₂ is downregulated. The major route of PGE₂ excretion is via the renal proximal tubular organic anion secretory system, where basolateral uptake that is mediated by renal organic anion transporter 1 (rOAT1) and rOAT3 is rate limiting. Therefore, it was hypothesized that PGE₂ itself will abolish its excretion by rOAT1 or rOAT3. Fluorescein was used as a prototypic organic anion, and NRK-52E cells from rat served as a proximal tubular model system. PGE₂ time-dependently downregulates basolateral organic anion uptake, without affecting cell volume or cell protein, recirculation of counter ions, or proximal tubular transport systems in general. In addition, PGE₂ diminishes expression of both rOAT1 and rOAT3. Both organic anion uptake and expression of rOAT1 and rOAT3 are dose-dependently downregulated by PGE₂. These findings suggest that during fever or inflammation, renal secretory transport of PGE₂ is reduced, contributing to elevated PGE₂ levels in blood. These data fit into the hypothetical concept of peripheral PGE₂’s playing a significant role in fever. The described regulatory mechanism may also be of relevance in chronic inflammatory events. Moreover, the data presented could explain why increased plasma urate levels occur in diseases that go along with increased levels of PGE₂.

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				R. Schneider, C. Sauvant, B. Betz, M. Otremba, D. Fischer, H. Holzinger, C. Wanner, J. Galle, and M. Gekle Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1599 - F1605. [Abstract] [Full Text] [PDF]

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