Organic anion transporters OAT1 and OAT4 mediate the high affinity transport of glutarate derivatives accumulating in patients with glutaric acidurias.
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.
Hagos
Yohannes
Y
Zentrum Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.
Krick
Wolfgang
W
Braulke
Thomas
T
Mühlhausen
Chris
C
Burckhardt
Gerhard
G
Burckhardt
Birgitta C
BC
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
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