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Human renal organic anion transporter 4 operates as an asymmetric urate transporter.
J Am Soc Nephrol. 2007 Feb; 18(2):430-9.JA

Abstract

Human organic anion transporter 4 (hOAT4) is located at the apical membrane of proximal tubule cells and involved in renal secretion and reabsorption of endogenous substances as well as many drugs and xenobiotics. This study reevaluated the physiologic role, transport mode, and driving forces of hOAT4. 6-Carboxyfluorescein (6-CF) uptake into HEK293 cells that stably expressed hOAT4 was saturable, resulting in a K(m) of 108 muM. 6-CF as well as [(3)H]estrone sulfate ([(3)H]ES) accumulation by HEK293-hOAT4 cells were abolished by ES, dehydroepiandrosterone sulfate, sulfinpyrazone, benzbromarone, and probenecid, whereas several OA, including p-aminohippurate (PAH), lactate, pyrazinoate, nicotinate, glutarate, and the diuretic hydrochlorothiazide (HCTZ) exhibited a slight or a NS inhibitory effect. PAH and glutarate are not taken up by HEK293-hOAT4 cells, but they trans-stimulated 6-CF and [(3)H]ES uptake, indicating an asymmetric interaction of hOAT4 with these substrates. In chloride-free medium, HEK293-hOAT4-mediated [(3)H]PAH efflux was almost abolished, whereas addition of ES restored it comparable to Ringer solution, consistent with a physiologic ES/PAH or PAH/Cl(-) exchange mode of hOAT4. Moreover, an acidification of the uptake medium increased 6-CF as well as [(3)H]ES uptake, which was reduced by nigericin, suggesting that hOAT4 also can operate as an OA/OH(-) exchanger. hOAT4 facilitates substantial uptake of [(14)C]urate, which was elevated 2.6-fold by intracellular HCTZ. Thus, hOAT4 is the long-postulated, low-affinity apical urate anion exchanger that facilitates HCTZ-associated hyperuricemia.

Authors+Show Affiliations

Zentrum für Physiologie und Pathophysiologie, Abt. Vegetative Physiologie und Pathophysiologie, Universität Göttingen, Humboldtallee 23, 37073 Göttingen, Germany. hagos@physiol.med.uni-goettingen.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17229912

Citation

Hagos, Yohannes, et al. "Human Renal Organic Anion Transporter 4 Operates as an Asymmetric Urate Transporter." Journal of the American Society of Nephrology : JASN, vol. 18, no. 2, 2007, pp. 430-9.
Hagos Y, Stein D, Ugele B, et al. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol. 2007;18(2):430-9.
Hagos, Y., Stein, D., Ugele, B., Burckhardt, G., & Bahn, A. (2007). Human renal organic anion transporter 4 operates as an asymmetric urate transporter. Journal of the American Society of Nephrology : JASN, 18(2), 430-9.
Hagos Y, et al. Human Renal Organic Anion Transporter 4 Operates as an Asymmetric Urate Transporter. J Am Soc Nephrol. 2007;18(2):430-9. PubMed PMID: 17229912.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human renal organic anion transporter 4 operates as an asymmetric urate transporter. AU - Hagos,Yohannes, AU - Stein,Daniel, AU - Ugele,Bernhard, AU - Burckhardt,Gerhard, AU - Bahn,Andrew, Y1 - 2007/01/17/ PY - 2007/1/19/pubmed PY - 2007/4/11/medline PY - 2007/1/19/entrez SP - 430 EP - 9 JF - Journal of the American Society of Nephrology : JASN JO - J Am Soc Nephrol VL - 18 IS - 2 N2 - Human organic anion transporter 4 (hOAT4) is located at the apical membrane of proximal tubule cells and involved in renal secretion and reabsorption of endogenous substances as well as many drugs and xenobiotics. This study reevaluated the physiologic role, transport mode, and driving forces of hOAT4. 6-Carboxyfluorescein (6-CF) uptake into HEK293 cells that stably expressed hOAT4 was saturable, resulting in a K(m) of 108 muM. 6-CF as well as [(3)H]estrone sulfate ([(3)H]ES) accumulation by HEK293-hOAT4 cells were abolished by ES, dehydroepiandrosterone sulfate, sulfinpyrazone, benzbromarone, and probenecid, whereas several OA, including p-aminohippurate (PAH), lactate, pyrazinoate, nicotinate, glutarate, and the diuretic hydrochlorothiazide (HCTZ) exhibited a slight or a NS inhibitory effect. PAH and glutarate are not taken up by HEK293-hOAT4 cells, but they trans-stimulated 6-CF and [(3)H]ES uptake, indicating an asymmetric interaction of hOAT4 with these substrates. In chloride-free medium, HEK293-hOAT4-mediated [(3)H]PAH efflux was almost abolished, whereas addition of ES restored it comparable to Ringer solution, consistent with a physiologic ES/PAH or PAH/Cl(-) exchange mode of hOAT4. Moreover, an acidification of the uptake medium increased 6-CF as well as [(3)H]ES uptake, which was reduced by nigericin, suggesting that hOAT4 also can operate as an OA/OH(-) exchanger. hOAT4 facilitates substantial uptake of [(14)C]urate, which was elevated 2.6-fold by intracellular HCTZ. Thus, hOAT4 is the long-postulated, low-affinity apical urate anion exchanger that facilitates HCTZ-associated hyperuricemia. SN - 1046-6673 UR - https://www.unboundmedicine.com/medline/citation/17229912/Human_renal_organic_anion_transporter_4_operates_as_an_asymmetric_urate_transporter_ L2 - https://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=17229912 DB - PRIME DP - Unbound Medicine ER -