Transport of organic anions across the basolateral membrane of proximal tubule cells

Abstract

Renal proximal tubules secrete diverse organic anions (OA) including widely prescribed anionic drugs. Here, we review the molecular properties of cloned transporters involved in uptake of OA from blood into proximal tubule cells and provide extensive lists of substrates handled by these transport systems. Where tested, transporters have been immunolocalized to the basolateral cell membrane. The sulfate anion transporter 1 (sat-1) cloned from human, rat and mouse, transported oxalate and sulfate. Drugs found earlier to interact with sulfate transport in vivo have not yet been tested with sat-1. The Na(+)-dicarboxylate cotransporter 3 (NaDC-3) was cloned from human, rat, mouse and flounder, and transported three Na(+) with one divalent di- or tricarboxylate, such as citric acid cycle intermediates and the heavy metal chelator 2,3-dimercaptosuccinate (succimer). The organic anion transporter 1 (OAT1) cloned from several species was shown to exchange extracellular OA against intracellular alpha-ketoglutarate. OAT1 translocated, e.g., anti-inflammatory drugs, antiviral drugs, beta-lactam antibiotics, loop diuretics, ochratoxin A, and p-aminohippurate. Several OA, including probenecid, inhibited OAT1. Human, rat and mouse OAT2 transported selected anti-inflammatory and antiviral drugs, methotrexate, ochratoxin A, and, with high affinities, prostaglandins E(2) and F(2alpha). OAT3 cloned from human, rat and mouse showed a substrate specificity overlapping with that of OAT1. In addition, OAT3 interacted with sulfated steroid hormones such as estrone-3-sulfate. The driving forces for OAT2 and OAT3, the relative contributions of all OA transporters to, and the impact of transporter regulation by protein kinases on renal drug excretion in vivo must be determined in future experiments.

Protein Kinase C Activation Downregulates Human Organic Anion Transporter 1-Mediated Transport through Carrier Internalization

“…A number of studies on intact renal proximal tubules (5,7) and renal proximal tubule cells in culture (9,33) have demonstrated PKC-dependent downregulation of the basolateral uptake of organic anions into cells, most likely mediated (at least in part) by the PAH-dicarboxylate exchanger OAT1 (2). How this downregulation is achieved is still unknown, however.…”

“…The renal secretory organic anion transport pathway plays an important role in the elimination of a variety of potentially toxic environmental chemicals, such as phenoxyacetate herbicides and fungicides, as well as anionic drugs, including ␤-lactam antibiotics, cytostatic agents, diuretics, and antiviral drugs (1,2). The importance of this pathway is exemplified by the increased toxicity of methotrexate when it is coadministered with nonsteroidal anti-inflammatory drugs (3), which compete for the same elimination pathway (4) and thus lead to higher serum methotrexate concentrations (3).…”

Renal organic anion transporters OAT1 and OAT3 mediate the cellular accumulation of 5-sulfooxymethylfurfural, a reactive, nephrotoxic metabolite of the Maillard product 5-hydroxymethylfurfural

“…The organic anion transporters OAT1 and OAT3 are localized at the basolateral membrane of proximal tubule cells and mediate the concentrative uptake of their substrates from blood into renal proximal tubule cells, which is the rate-limiting step in this excretion system [14]. Genes of both transporters were cloned from several species, including rat and man, and are highly conserved across species [14,15]. Both transporters show overlapping substrate specificities and share the driving force -exchange of organic anions against intracellular α-ketoglutarate.…”

Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid

“…VanWert et al found that ciprofloxacin was transported by OAT3 and ciprofloxacin, norfloxacin, ofloxacin and gatifloxacin inhibited OAT3 [31]. Ciprofloxacin did not interact with OAT1, while probenecid inhibits both OAT1 and OAT3 [31,32]. Also, involvement of OCT was reported for ciprofloxacin [31] as for probenecid.Therefore an OAT, e.g.…”