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

Abstract

Prostaglandin E 2 (PGE 2 ) is the principal mediator of fever and inflammation. Recently, evidence emerged that during febrile response, PGE 2 that is generated in the periphery enters the hypothalamus and contributes to the maintenance of fever. In a rat model of fever generation, peripheral PGE 2 is increased, whereas clearance by metabolism of peripheral PGE 2 is downregulated. The major route of PGE 2 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 PGE 2 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. PGE 2 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, PGE 2 diminishes expression of both rOAT1 and rOAT3. Both organic anion uptake and expression of rOAT1 and rOAT3 are dose-dependently downregulated by PGE 2 . These findings suggest that during fever or inflammation, renal secretory transport of PGE 2 is reduced, contributing to elevated PGE 2 levels in blood. These data fit into the hypothetical concept of peripheral PGE 2 '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 PGE 2 .J Am Soc Nephrol 17: 46 -53, 200646 -53, . doi: 10.1681 T he organic anion transport system of the renal proximal tubule plays a crucial role in the excretion of a variety of potentially toxic compounds. This system consists of organic anion exchangers that are located at the basolateral membrane and a less well-characterized transport step at the apical membrane. The classical basolateral organic anion exchanger is the terminal step in a tertiary active transport system, dependent on an inward-directed Na ϩ gradient to drive the uptake of ␣-ketoglutarate, which then is exchanged for organic anions. It has been shown that OAT1 represents characteristics of the basolateral, polyspecific transporter for organic anions, which had been functionally described for some time (1). Recently, new evidence has indicated that organic anion transporter 3 (OAT3) (2), which also is located in the basolateral renal proximal tubular membrane, also works as an appropriate exchanger for organic anions and dicarboxylates (3,4). Moreover, additional homologues have been cloned and were called OAT2 (5), OAT4 (6), OAT5 (7), and OAT6 (8). These clones show 40 to 60% homology in amino acid sequence compared with OAT1 or OAT3, and they differ in substrate specificity and expression pattern. Furthermore, these latter proteins are not anion exchangers like OAT1 or OAT3 but seem to work as fac...

Organic anion transporters OAT1 and OAT4 mediate the high affinity transport of glutarate derivatives accumulating in patients with glutaric acidurias

“…The coordinated action of these transporters may guarantee a high renal clearance of GA and GA derivatives under metabolically stable conditions. In states of fever, however, downregulation of the expression of OAT1 [27] may partially impair renal secretion and cause accumulation of GA derivatives with possible side effects. Fig.…”

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

“…It should be noted, however, that controversy exists, particularly regarding the role of PGE 2 . For example, in a separate study downregulation of basolateral fluorescein uptake and of rOat1 and rOat3 protein expression was observed in NRK-52E cells (rat renal proximal tubule cell line) treated with PGE 2 [109]. Thus, there is a clear need to further define the role of PGE 2 in OAT regulation.…”

Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors

“…4,5 In contrast, long-term exposure to PGE 2 inhibits its excretion by decreasing the levels of basolateral organic anion transporters that are responsible for PGE 2 uptake in rat renal PT cells. 6 The underlying regulatory pathways are not completely understood, but short-term vs long-term exposure to PGE 2 has opposite effects on the overall cell response. PGE 2 also reduces phosphate transport in mouse proximal convoluted tubules.…”