A Novel Transporter of SLC22 Family Specifically Transports Prostaglandins and Co-localizes with 15-Hydroxyprostaglandin Dehydrogenase in Renal Proximal Tubules

Abstract

We identified a novel prostaglandin (PG)-specific organic anion transporter (OAT) in the OAT group of the SLC22 family. The transporter designated OAT-PG from mouse kidney exhibited Na ؉ -independent and saturable transport of PGE 2 when expressed in a proximal tubule cell line (S 2 ). Unusual for OAT members, OAT-PG showed narrow substrate selectivity and high affinity for a specific subset of PGs, including PGE 2 , PGF 2␣ , and PGD 2 . Similar to PGE 2 receptor and PGT, a structurally distinct PG transporter, OAT-PG requires for its substrates an ␣-carboxyl group, with a double bond between C13 and C14 as well as a (S)-hydroxyl group at C15. Unlike the PGE 2 receptor, however, the hydroxyl group at C11 in a cyclopentane ring is not essential for OAT-PG substrates. Addition of a hydroxyl group at C19 or C20 impairs the interaction with OAT-PG, whereas an ethyl group at C20 enhances the interaction, suggesting the importance of hydrophobicity around the -tail tip forming a "hydrophobic core" accompanied by a negative charge, which is essential for substrates of OAT members. OAT-PG-mediated transport is concentrative in nature, although OAT-PG mediates both facilitative and exchange transport. OAT-PG is kidney-specific and localized on the basolateral membrane of proximal tubules where a PG-inactivating enzyme, 15-hydroxyprostaglandin dehydrogenase, is expressed. Because of the fact that 15-keto-PGE 2 , the metabolite of PGE 2 produced by 15-hydroxyprostaglandin dehydrogenase, is not a substrate of OAT-PG, the transport-metabolism coupling would make unidirectional PGE 2 transport more efficient. By removing extracellular PGE 2 , OAT-PG is proposed to be involved in the local PGE 2 clearance and metabolism for the inactivation of PG signals in the kidney cortex.

Remote Communication through Solute Carriers and ATP Binding Cassette Drug Transporter Pathways: An Update on the Remote Sensing and Signaling Hypothesis

“…Their tissue distribution seems consistent with the fact that prostaglandins, which act via paracrine or autocrine regulation, are able to be removed locally to keep the systemic circulating levels low. The recent identification of a renal-specific prostaglandin transporter, OAT-PG in the SLC22 family, suggests how the uptake and elimination may be coordinately handled (Shiraya et al, 2010). Unlike other PG transporters, OAT-PG has narrower substrate specificities with a preference for PGE2, PGF2a, and PGD2.…”

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…Several OAT isoforms appear somewhat specialized for transport of classic signaling molecules and antioxidants and therefore well suited for signaling: liver-expressed OAT2 transports cyclic guanosine monophosphate (107), placentalexpressed OAT4 transports conjugated estrogens (108), olfactory-expressed OAT6 has high selectivity for odorants (109), and OATPG seems specialized for prostaglandins (110). The drug transporters mediating the influx and efflux through tissues and body fluid compartments (e.g., blood, urine, bile, cerebrospinal fluid, and amniotic fluid) could regulate remote communication via transport of key (potentially rate-limiting) metabolites and signaling molecules, hence regulating the movement of these molecules across tissue barriers in the body and also at the cellular level.…”

Decreased Expression of a Novel Prostaglandin Transporter, OAT-PG, Facilitates Renocortical PGE₂ Accumulation during Rat Pregnancy

“…1a). To reveal the underlying mechanism of this increase, we examined the expression of OAT-PG, a recently identified renal transporter involved in the local clearance of PGE 2 in proximal tubules [12,13]. On gestational day 7, the cortical expression of OAT-PG mRNA in rat kidneys was significantly decreased from that of the virgin value (fig.…”

“…Although these findings suggested an increased level of the renocortical PGE 2 content, later studies revealed unaltered biosynthesis of PGE 2 in pregnant rat kidneys [11]. Recently, we identified a novel PG-specific organic anion transporter (OAT), OAT-PG, exclusively expressed in renal proximal tubules [12]. Later, we further revealed its functional significance in the clearance of renal PGE 2 , demonstrating that renal expression of this transporter primarily determines the renocortical PGE 2 content [13].…”