The theory of the "four-component model" of urate excretion in humans is reevaluated, considering that a decrease in urate excretion induced by drugs like pyrazinamide or by endogenous compounds like lactate and ketone bodies might be a result of stimulation of urate reabsorption and not, as previously considered, of inhibition of urate secretion.

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.

Effects of mineralocorticoid and K ϩ concentration on K ϩ secretion and ROMK channel expression in a mouse cortical collecting duct cell line.

[14C]urate and p-[14C]aminohippurate (PAH) uptake by human brush-border membrane vesicles (BBMV) were measured in the presence of an inwardly oriented sodium gradient. No direct sodium cotransport was observed. Indirect [14C]urate coupling to sodium transport was demonstrated by cis-stimulation of [14C]urate with nicotinate or pyrazinoate (PZA) in the extravesicular medium but not by adding lactate, alpha-ketoglutarate, or beta-hydroxybutyrate. Indirect sodium coupling of [14C]PAH uptake was observed only when alpha-ketoglutarate was added to the extravesicular medium, a mechanism similar to that of basolateral membranes. The ability for PZA (and nicotinate) to cis-stimulate urate uptake was correlated with a high apparent affinity for the urate/anion exchanger. In urate-loaded vesicles, for identical medium concentrations, [14C]PZA uptake via the urateanion exchanger was 10 times higher than [14C]lactate uptake. Such high PZA affinity for the urate exchanger, working in parallel with PZA sodium cotransport can account for the stimulation of urate reabsorption by PZA in vivo.

Earlier studies demonstrated that an apical anion exchanger which accepts urate, chloride, aliphatic monocarboxylates, and the aromatic anions, pyrazinoate (PZA) and nicotinate, plays a major role in urate reabsorption in human proximal tubules. In substrate competition studies for transport, we investigated the effect of PZA on 50 µM [¹⁴C]-urate uptake in exchange of lactate, human brush-border membrane vesicles (BBMV) being loaded with 5 mM lactate. 1 mM PZA cis-inhibited, whereas 0.1 mM PZA cis-stimulated [¹⁴C]-urate uptake in exchange for lactate. Such paradoxical effects suggest the cooperation of two anion exchangers, PZA having more affinity for a ‘lactate/anion exchanger’ than for a ‘urate/ anion exchanger’. Apparent K_m of [¹⁴C]-PZA uptake were measured in lactate- or urate-loaded BBMV, and were 0.33 ± 0.06 and 0.98 ± 0.44 mM, respectively. Unlike [¹⁴C]-PZA, [¹⁴C]-orotate and [¹⁴C]-nicotinate uptakes were stimulated only to a minor extent in BBMV loaded with lactate. In contrast, cis -inhibition studies in urate-loaded BBMV demonstrated that nicotinate and orotate had similar affinity as PZA for the ‘urate/anion exchanger’. Oxalate was shown to have affinity for the ‘lactate/anion exchanger’, but not for the ‘urate/anion exchanger’.