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, 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.

Glutaric Aciduria Type 1 Metabolites Impair the Succinate Transport from Astrocytic to Neuronal Cells

“…The reduced efflux rate of succinate from Gcdh Ϫ/Ϫ astrocytic cells might be either the result of a cis-inhibition by the dicarboxylates GA and/or 3OHGA accumulating intracellularly (15) Taken together, our results show that the export of the TCA cycle intermediate succinate from Gcdh Ϫ/Ϫ astrocytic cells is impaired. Furthermore, its subsequent uptake into neuronal cells, which is most likely mediated by NaC2 and/or NaC3 (17,23,30; this report), can be inhibited by GA and 3OHGA accumulating in the extracellular fluid.…”

“…4 Although the identity of the transporter mediating the efflux of succinate from astroglial cells is not known, a member of the organic anion transporter (OAT) family, Oat1, was considered a potential candidate (32). Expression studies provided evidence that Oat1 transports both succinate as well as GA and 3OHGA across membranes (15,33) and is expressed in the brain (34 -36). Quantitative mRNA expression analyses, however, in primary cultured brain cells from wild-type and Gcdh Ϫ/Ϫ mice demonstrated that Oat1 was expressed in neuronal cells only.…”

“…Recently, we have shown that NaC3 is capable of transporting both GA and 3OHGA (14,15). The ability of these metabolites to inhibit sodium-dependent […”

“…Recently, we have shown that NaC3 is capable of transporting the dicarboxylates GA and 3OHGA (14,15), pathologic metabolites that accumulate in body fluids and tissues, espe- Efflux experiments were performed as described under "Experimental Procedures" and in the legend to Fig. 3.…”

“…Recently, we identified the sodium-dependent dicarboxylate co-transporter 3 (NaC3) and organic anion transporters (OAT) 1 and 4 as low and high affinity transporters, respectively, for the translocation of GA and 3OHGA through membranes (14,15). The concerted action of NaC3, OAT1, and OAT4 in renal proximal tubule cells may be important for the urinary excretion of GA and 3OHGA (16).…”