Cellular response to oxygen depletion is mediated by hypoxia-inducible transcription factors (HIFs). Stability of the oxygen-regulated subunit of the HIFs is influenced by prolyl-4-hydroxylases (PHDs). a-ketoglutarate (aKG) analogues were used as PHD inhibitors stabilizing HIF. Basolateral uptake of aKG in proximal tubule cells is mediated by the sodium-dicarboxylate cotransporter 3 (NaDC3) and the organic anion transporters 1 and 3 (OAT1, OAT3). Release of aKG occurs via luminal OAT4. We examined the interaction of the PHD inhibitors N-oxalylglycine (NOG), dimethyloxalyl glycine (DMOG), 2,4-diethylpyridine dicarboxylate (2,4-DPD), and pyridine dicarboxylic acid (PDCA) with NaDC3, OAT1, OAT3, and OAT4 stably transfected in HEK293 cells. While NOG, DMOG, 2,4-DPD, and PDCA did not interact with NaDC3, OAT3, and OAT4 in cis-inhibition experiments, uptake of p-aminohippurate by OAT1 was inhibited by NOG, 2,4-DPD, and PDCA with a K_i of 353, 38, and 20 mM, respectively. Uptake of estrone sulfate by OAT4 was trans-stimulated by DMOG and 2,4-DPD. Using western blot analysis, the selective OAT1-mediated uptake of NOG, PDCA, and 2,4-DPD was confirmed by demonstration of HIF stabilization only in OAT1-transfected cells. Thus OAT1 is a pharmacological target for PHD inhibitors. In addition OAT1 and OAT4 are responsible for the secretion of these PHD inhibitors into the urine. Supported by DFG BU 998/5-1