title: Organic anion transporters OAT1 and OAT4 mediate the high affinity transport of glutarate derivatives accumulating in patients with glutaric acidurias.
abstract: Glutaric acidurias are rare inherited neurodegenerative disorders accompanied by accumulation of the metabolites glutarate (GA) and 3-hydroxyglutarate (3OHGA), glutaconate, L: -, or D: -2-hydroxyglutarate (L: -2OHGA, D: -2OHGA) in all body fluids. Oocytes expressing the human (h) sodium-dicarboxylate cotransporter (NaDC3) showed sodium-dependent inward currents mediated by GA, 3OHGA, L: -, and D: -2OHGA. The organic anion transporters (OATs) were examined as additional transporters for GA derivatives. The uptake of [(3)H]p-aminohippurate in hOAT1-transfected human embryonic kidney (HEK293) cells was inhibited by GA, 3OHGA, D: -, or L: -2OHGA in a concentration-dependent manner. None of these compounds affected the hOAT3-mediated uptake of [(3)H]estrone sulfate (ES). In hOAT4-expressing cells and oocytes, ES uptake was strongly increased by intracellular GA derivatives. The data provide a model for the concerted action of OAT1 and NaDC3 mediating the basolateral uptake, and OAT4 mediating apical secretion of GA derivatives from proximal tubule cells and therefore contribute to the renal clearance of these compounds.
authors: Zentrum Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.
authors: Yohannes
authors: Y
authors: Hagos
authors: Wolfgang
authors: W
authors: Krick
authors: Thomas
authors: T
authors: Braulke
authors: Chris
authors: C
authors: Mühlhausen
authors: Gerhard
authors: G
authors: Burckhardt
authors: Birgitta C
authors: BC
authors: Burckhardt
mesh_terms: D000818:Animals; D002460:Cell Line; D029382:Dicarboxylic Acid Transporters / Q000378:metabolism; D004970:Estrone / Q000502:physiology; D005260:Female; D005977:Glutarates / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000502:physiology*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000502:physiology*; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013379:Substrate Specificity / Q000502:physiology; D027981:Symporters / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D029382:Dicarboxylic Acid Transporters; D005977:Glutarates; D027362:Organic Anion Transport Protein 1; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D018075:RNA, Complementary; C092524:SLC13A2 protein, human; C427207:SLC22A11 protein, human; D015222:Sodium Channels; D027981:Symporters; C114338:organic anion transport protein 3; C019417:alpha-hydroxyglutarate; D004970:Estrone; D010130:p-Aminohippuric Acid