α-Ketoglutarate-related inhibitors of HIF prolyl hydroxylases are substrates of renal organic anion transporters 1 OAT1 and 4 OAT4Report as inadecuate




α-Ketoglutarate-related inhibitors of HIF prolyl hydroxylases are substrates of renal organic anion transporters 1 OAT1 and 4 OAT4 - Download this document for free, or read online. Document in PDF available to download.

Pflügers Archiv - European Journal of Physiology

, Volume 464, Issue 4, pp 367–374

First Online: 09 August 2012Received: 09 March 2012Revised: 19 June 2012Accepted: 24 July 2012

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.

KeywordsHypoxia-inducible factor Prolyl hydroxylase domains Organic anion transport Proximal tubule  Download fulltext PDF



Author: Yohannes Hagos - Gunnar Schley - Johannes Schödel - Wolfgang Krick - Gerhard Burckhardt - Carsten Willam - Birgitta C. Bu

Source: https://link.springer.com/







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