Urate transport in brush-border membrane of human kidney

Abstract

Mechanisms of urate transport were investigated in human renal brush-border membrane vesicles. The imposition of an outwardly directed Cl- gradient, in voltage-clamp and pH-clamp conditions, stimulated [14C]urate uptake. Organic anions, including pyrazinoate (PZA), probenecid, lactate, ketone bodies, succinate, and alpha-ketoglutarate in their monovalent forms, cis-inhibited [14C]urate uptake. The affinity order was PZA > urate > probenecid > other anions. Vesicle preloading with these anions trans-stimulated urate uptake. These observations demonstrate the presence of a urate/anion exchanger. p-Aminohippurate and OH- were not substrates for this exchanger. In the presence of an inwardly directed K+ gradient and valinomycin (intravesicular positive potential) [14C]urate uptake was stimulated. Voltage-sensitive [14C]urate uptake was cis-inhibited by organic anions in the following affinity order: urate > probenecid > PZA. The differences in affinity orders for the urate exchanger and the urate voltage-sensitive transport suggest different pathways for apical transport. The anion exchanger might be the main mechanism involved in urate tubular reabsorption in humans.

Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter

“…Based on our current findings (Figures 2-5) we conclude galectin 9 need not invariably be a cytoplasmic or secreted protein, but rather that it may reside as an integral protein in the lipid bilayer of plasma membranes where it may serve an important transport function, at least in renal epithelial cells. Additionally, insofar as recombinant hUAT functions as a selective urate channel (Figure 2), we suggest that hUAT is likely to be the molecular representation of the electrogenic transporter that functions to secrete urate into the proximal tubule of the human kidney (13). Since excreted urate is generally thought to derive primarily from secreted urate (45,46), perturbations in this transporter could modify the ability of the kidney to eliminate urate from the body.…”

Human Renal Organic Anion Transporter 4 Operates as an Asymmetric Urate Transporter

“…Urate uptake into human renal BBMV was noted to be strongly stimulated by an outwardly directed Cl Ϫ gradient (19).…”

“…In earlier vesicle studies, Roch-Ramel et al (19) postulated the existence of two different urate exchangers, one with high affinity for urate and aromatic molecules, such as nicotinate, pyrazinoate, and orotate, which now is represented by hURAT1, and a second, low-affinity urate transporter that exchanges urate against OA or chloride (27). Moreover, they demonstrated that an OH Ϫ ion gradient provokes urate uptake into human brush border membrane vesicles (BBMV), a transport mode, which is not covered by hURAT1 (11).…”

Transepithelial urate transport by avian renal proximal tubule epithelium in primary culture

“…However, no chicken orthologs of these two transporters have yet been identified; they are Cl -sensitive and they do not have the BBMV urate transport properties, i.e. they are not electrogenic antiporters (Roch-Ramel et al, 1994).…”

“…Among the vertebrates, the modalities of urate transport across the apical membranes of the proximal tubule epithelium include electroneutral anion exchange (Enomoto et al, 2002;Guggino et al, 1983), electrogenic urate transport (Grassl, 2002a;Roch-Ramel et al, 1994) and primary active transport (Van Aubel et al, 2005). The last two processes have been associated with urate secretion, and NPT1 (sodium-phosphate transporter I; Uchino et al, 2000), Oat v 1 (voltage-dependent organic anion transporter 1; Jutabha et al, 2003) and MRP4 (multidrug resistance peptide 4; Van Aubel et al, 2005) have been proposed as candidate transporters.…”