title: α-Ketoglutarate-related inhibitors of HIF prolyl hydroxylases are substrates of renal organic anion transporters 1 (OAT1) and 4 (OAT4).
abstract: 2-Oxoglutarate or α-ketoglutarate (αKG) is a substrate of HIF prolyl hydroxylases 1-3 that decrease cellular levels of the hypoxia-inducible factor 1α (HIF-1α) in the presence of oxygen. αKG analogs are applied to stabilize HIF-1α even in the presence of oxygen and thus provide a novel therapeutic option in treating kidney diseases. In the kidneys, the organic anion transporters 1 and 3 (OAT1 and OAT3, respectively) in cooperation with the sodium-dependent dicarboxylate transporter 3 (NaDC3) and the OAT4 might be responsible for the uptake of αKG analogs into and the efflux out of the tubular cells. Using the radiolabelled substrates p-aminohippurate (PAH, OAT1), estrone-3-sulfate (ES; OAT3, OAT4), and succinate (NaDC3), N-oxalylglycine (NOG), dimethyloxalyl glycine (DMOG), 2,4-diethylpyridine dicarboxylate (2,4-DPD), and pyridine-2,4-dicarboxylic acid (PDCA) were tested in cis-inhibition and trans-stimulation experiments. None of these αKG analogs interacted with NaDC3. 2,4-DPD and PDCA inhibited ES uptake by OAT3 moderately. NOG, 2,4-DPD and PDCA, but not DMOG, inhibited PAH uptake by OAT1 significantly. trans-Stimulation experiments and experiments demonstrating stabilization of HIF-1α revealed that NOG and PDCA, but not 2,4-DPD, are translocated by OAT1. All compounds trans-stimulated ES uptake by OAT4, but only PDCA stabilized HIF-1α. The data suggest that OAT1 is involved in the uptake of NOG and PDCA across the basolateral membrane of proximal tubule cells, whereas OAT4 may release these compounds into the primary urine.
authors.affiliation: Department of Systemic Physiology and Pathophysiology, University Medical Center Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Hagos
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schley
authors.forename: Johannes
authors.initials: J
authors.lastname: Schödel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Krick
authors.forename: Gerhard
authors.initials: G
authors.lastname: Burckhardt
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
authors.forename: Birgitta C
authors.initials: BC
authors.lastname: Burckhardt
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000378:metabolism; D001693:Biological Transport, Active; D049308:Dioxygenases / Q000037:antagonists & inhibitors*; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism*; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000187:drug effects / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000187:drug effects / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism; D027981:Symporters / Q000187:drug effects / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D000600:Amino Acids, Dicarboxylic; D051793:Hypoxia-Inducible Factor 1; D007656:Ketoglutaric Acids; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D011725:Pyridines; C568530:SLC13A3 protein, human; D027981:Symporters; D004970:Estrone; C055293:2,4-pyridinedicarboxylic acid; D019802:Succinic Acid; D049308:Dioxygenases; D011393:Procollagen-Proline Dioxygenase; C017296:estrone sulfate; C040947:oxalylglycine; D010130:p-Aminohippuric Acid