Nature of urate transport in isolated rabbit proximal tubules

Abstract

Unidirectional fluxes of [14C]-urate from bath to lumen and from lumen to bath were measured in isolated perfused rabbit proximal tubules. The absorption of urate from the perfusate was small in magnitude and relatively insensitive to alteration by luminal probenecid or D-glucose. By contrast, peritubular probenecid inhibited urate secretion from bath to lumen in all three segments. To estimate the facilitated component of urate secretion for each bath concentration of the anion, the passive component of urate influx (probenecid-resistant influx) was subtracted from the total influx of urate. Urate secretion was strongly dependent on concentration of urate in the bath, the relationship being sigmoidal in many S1 and S2 segments. The S0.5 values of 187,251, and 234 X 10(-6) M obtained from Hill plots of mean data from S1, S2, S3 segments, respectively, indicated that the secretory mechanism had a relatively uniform affinity for urate along the proximal tubule. Vmax values for urate secretion were 568,592, and 55 X 10(-15) mol . min-1 . mm-1 for the same segments. Kinetic analysis indicated that axial heterogeneity of urate secretion is probably due to differences in the relative densities of urate transporters of common affinity along the proximal tubule. We suggest that in intact rabbits with low plasma levels urinary urate is the product of glomerular filtration, passive reabsorption, and minimal proximal secretion. With elevation of plasma urate above endogenous levels, S1 and S2 segments secrete urate at an accelerated rate, possibly reflecting action of a transporter with allosteric features.

Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes.

“…In contrast, pyrazinoate does not reduce urate excretion in the rabbit (18). Rabbit proximal tubules secrete urate actively but have no mediated urate reabsorption (19,20 …”

Renal Tubular Hypouricemia: Evidence for Defect of Both Secretion and Reabsorption

“…Renal excretion of uric acid is thought to be derived from the following sources; uric acid filtred at the glom erulus is extensively reabsorbed [13][14][15][16], and uric acid secreted massively at a site distal to this reabsorption [17][18][19] is again reabsorbed [20][21][22], Thus, in normal sub jects, the excreted urate respresents mainly that fraction of secretd urate which escapes postsecretory reabsorp tion [23][24][25][26], This four-compartment model has been sup ported by a number of clinical observations. In accord ance with this model, four types of renal tubular urate transport abnormalities have been proposed to cause hypouricemia to date: (1) presecretory reabsorptive de fect when an attenuated response to pyrazinamide and probenecid is observed [1-3, 27, 28]; (2) postsecretory reabsorptive defect when pyrazinamide suppresses in creased Cua, while probenecid produces no increase [29,30]; (3) association of presecretory and postsecretory reabsorptive defect when Cua exceeding the glomerular filtration rate is eliminated by pyrazinamide [31,32]; (4) and increased secretion when Cua is supressed by pyra zinamide and shows a further marked increase after probenecid [4,6,[10][11][12]33].…”

Renal Hypouricemia with Both Drug-Insensitive Secretion and Defective Reabsorption of Urate: A Novel Type of Renal Hypouricemia

“…The present concept of renal tubular urate handling proposes a four-component model: glomerular filtration, presecretory tubular reabsorption [19], tubular secretion [20] and postsecretory reabsorption [21], as shown in figure la. Thus far, four types of defect causing renal hypouricemia have been classified depending on the response of urate excretion to pyrazinamide and to probenecid.…”