Prostaglandin E2 inhibits its own renal transport by downregulation of organic anion transporters rOAT1 and rOAT3.
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.
Sauvant
Christoph
C
Physiologisches Institut der Universität Würzburg, Röntgenring 9, 97070 Würzburg, Germany. christoph.sauvant@mail.uni-wuerzburg.de
Holzinger
Hildegard
H
Gekle
Michael
M
D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats
D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C421043:Slc22a6 protein, rat; C114338:organic anion transport protein 3; D015232:Dinoprostone