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Multiple organic anion transporters contribute to net renal excretion of uric acid.

ABSTRACT: Excretion of uric acid, a compound of considerable medical importance, is largely determined by the balance between renal secretion and reabsorption. The latter process has been suggested to be principally mediated by urate transporter 1 (URAT1; slc22a12), but the role of various putative urate transporters has been much debated. We have characterized urate handling in mice null for RST, the murine ortholog of URAT1, as well as in those null for the related organic anion transporters Oat1 and Oat3. Expression of mRNA of other putative urate transporters (UAT, MRP2, MRP4, Oatv1) was unaffected in the knockouts, as were general indexes of renal function (glomerular filtration rate, fractional excretion of fluid and electrolytes). While mass spectrometric analyses of urine and plasma revealed significantly diminished renal reabsorption of urate in RST-null mice, the bulk of reabsorption, surprisingly, was preserved. Oat1- and Oat3-null mice manifested decreased secretion rather than reabsorption, indicating that these related transporters transport urate in the "opposite" direction to RST. Moreover, metabolomic analyses revealed significant alteration in the concentration of several molecules in the plasma and urine of RST knockouts, some of which may represent additional substrates of RST. The results suggest that RST, Oat1, and Oat3 each contribute to urate handling, but, at least in mice, the bulk of reabsorption is mediated by a transporter(s) that remains to be identified. We discuss the data in the context of recent human genetic studies that suggest that the magnitude of the contribution of URAT1 to urate reabsorption might vary with ethnic background.

SUBMITTER: Eraly SA

PROVIDER: S-EPMC3016923 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Multiple organic anion transporters contribute to net renal excretion of uric acid.

Eraly Satish A SA Vallon Volker V Rieg Timo T Gangoiti Jon A JA Wikoff William R WR Siuzdak Gary G Barshop Bruce A BA Nigam Sanjay K SK

Physiological genomics 20080212 2

Excretion of uric acid, a compound of considerable medical importance, is largely determined by the balance between renal secretion and reabsorption. The latter process has been suggested to be principally mediated by urate transporter 1 (URAT1; slc22a12), but the role of various putative urate transporters has been much debated. We have characterized urate handling in mice null for RST, the murine ortholog of URAT1, as well as in those null for the related organic anion transporters Oat1 and Oa ...[more]

PMID: 18270321

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Project description:Background and objectivesIdiopathic uric acid nephrolithiasis, which is closely associated with obesity and the metabolic syndrome, is increasing in prevalence. Unduly acidic urine pH, the quintessential pathophysiologic feature of this disease, is in part explained by inadequate excretion of the principal urinary buffer ammonium. The role of net acid excretion in the pathogenesis of uric acid nephrolithiasis is incompletely understood.Design, setting, participants, & measurementsWe compared acid-base parameters of patients with idiopathic uric acid nephrolithiasis with matched control subjects under controlled diets in an inpatient metabolic unit. Measurements included fasting blood and 24-hour urine chemistries and 24-hour urine metabolomic analysis. Comparisons between groups included analysis of covariance models controlling for urine pH or body mass index.ResultsSubjects with idiopathic uric acid nephrolithiasis had lower urine pH (5.5 versus 5.9; P<0.001) and higher net acid excretion (60 versus 43 mEq/24 h; P<0.001), with the excess H+ carried by nonammonium buffers. In all subjects, there was a positive relationship of net acid excretion with higher body mass index in spite of strictly controlled equivalent dietary acid intake. This relationship was most evident among control subjects (r=0.36; P=0.03). It was attenuated in patients with idiopathic uric acid nephrolithiasis whose net acid excretion remained fixedly high and ammonium excretion remained low relative to net acid excretion, resulting in low urine pH over a wide body mass index range. Urinary metabolomics was performed to attempt to identify excess organic acids presented to the kidney in idiopathic uric acid nephrolithiasis. Among the tricarboxylic acid cycle intermediates and amino acid and lipid metabolites analyzed, 26 organic anions with acid dissociation constants values in the range of urine pH showed greater protonation. However, protons carried by the identified organic acids did not entirely account for the higher titratable acidity seen in idiopathic uric acid nephrolithiasis.ConclusionsHigher acid load to the kidney, resulting in higher urinary net acid excretion, is an important factor in the pathogenesis of idiopathic uric acid nephrolithiasis.

Project description:BackgroundBreast cancer resistance protein (BCRP) and multidrug resistance protein 4 (MRP4) are involved in uric acid excretion in humans and mice. Despite evidence suggesting that renal proximal tubular epithelial cells participate in uric acid excretion in chickens, the roles of BCRP and MRP4 therein remain unclear. This study evaluated the relationship between BCRP and MRP4 expression and renal function in chickens.ResultsSixty laying hens were randomly divided into four treatment groups: a control group (NC) fed a basal diet; a sulfonamide-treated group (SD) fed the basal diet and supplemented with sulfamonomethoxine sodium via drinking water (8 mg/L); a fish meal group (FM) fed the basal diet supplemented with 16% fishmeal; and a uric acid injection group (IU) fed the basal diet and intraperitoneally injected with uric acid (250 mg/kg body weight). The results showed that serum uric acid, creatinine, and blood urea nitrogen levels were significantly higher in the SD and IU, but not FM, than in the NC groups. Renal tubular epithelial cells in the SD and IU groups were damaged. Liver BCRP and MRP4 mRNA and protein levels were significantly decreased in the SD and IU groups, but slightly increased in the FM group. In the SD group, BCRP and MRP4 were significantly increased in the ileum and slightly increased in the kidney. In the FM group, BCRP and MRP4 were significantly increased in the kidney and slightly increased in the ileum. In the IU group, BCRP and MRP4 were significantly increased in the kidney and ileum. BCRP and MRP4 expression in the jejunum was not affected by the treatments.ConclusionTogether, these results demonstrate that BCRP and MRP4 are involved in renal and intestinal uric acid excretion in chickens and that BCRP is positively related to MRP4 expression. Further, impairment of renal function results in an increase in serum uric acid as well as a compensatory increase in BCRP and MRP4 in the ileum; however, under normal renal function, renal BCRP and MRP4 are the main regulators of uric acid excretion.

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Multiple organic anion transporters contribute to net renal excretion of uric acid.

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Multiple organic anion transporters contribute to net renal excretion of uric acid.

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