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

Eraly, Satish A.; Vallon, Volker; Rieg, Timo; Gangoiti, Jon A.; Wikoff, William R.; Siuzdak, Gary; Barshop, Bruce A.; Nigám, Sanjay K.

doi:10.1152/physiolgenomics.00207.2007

Cited by 216 publications

(191 citation statements)

References 68 publications

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“…More recent findings have indicated that several transporters, on both apical and basolateral membranes, are likely important determinants of uric acid blood levels. That is, Urat1, Oat1 and Oat3 each appeared to contribute to uric acid levels when evaluated in transporternull mice [93]. In addition, evidence suggests that at least one other carrier protein is involved in mediating the reabsorption of uric acid in mice [93].…”

Section: Urat1 (Slc22a12)mentioning

confidence: 95%

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

222

238

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Our understanding of the mechanisms behind inter-and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient-and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender.

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Section: Urat1 (Slc22a12)mentioning

confidence: 95%

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

222

238

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“…Knockout of the Urat1 gene in the mouse leads to increased urate excretion but no significant hypouricemia, indicating that in the mouse, this transporter plays a less important role than in humans for the control of uricemia (56).…”

Section: Urate Transporting Proteins and Genetics Of Urate Transportementioning

confidence: 99%

“…However, Oat3 is also found in all segments of the rat nephron from the proximal tubule to the collecting duct (65). Gene knockout studies in the mouse indicate that absence of OAT1 or OAT3 slightly decreases uricosuria, suggesting that their principal function is in urate excretion (56).…”

Section: Figurementioning

confidence: 99%

Uric acid transport and disease

Thorens²

2010

J. Clin. Invest.

692

496

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Uric acid is the metabolic end product of purine metabolism in humans. It has antioxidant properties that may be protective but can also be pro-oxidant, depending on its chemical microenvironment. Hyperuricemia predisposes to disease through the formation of urate crystals that cause gout, but hyperuricemia, independent of crystal formation, has also been linked with hypertension, atherosclerosis, insulin resistance, and diabetes. We discuss here the biology of urate metabolism and its role in disease. We also cover the genetics of urate transport, including URAT1, and recent studies identifying SLC2A9, which encodes the glucose transporter family isoform Glut9, as a major determinant of plasma uric acid levels and of gout development.Conflict of interest: Alexander So has acted as a consultant and advisor for Novartis.Citation for this article:

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“…The urate/anion exchanger URAT1 plays an important role in urate reabsorption across the apical membrane of proximal tubular epithelial cells. Mutations in URAT1 cause hypouricemia in humans (9), further Urat1 gene knockout in the mouse leads to mild hypouricemia and increased urate excretion (10). The apical membrane organic anion transporter OAT4 may also transport urate (11).…”

mentioning

confidence: 99%

“…The basolateral membrane organic anion transporters OAT1 and OAT3 also transport urate (13,14). However, inactivation of either OAT1 or OAT3 slightly decreases uricosuria, suggesting that their principal function may be in urate excretion (10).…”

mentioning

confidence: 99%

Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy

Preitner¹,

Bonny²,

Laverrière

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

231

184

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Elevated plasma urate levels are associated with metabolic, cardiovascular, and renal diseases. Urate may also form crystals, which can be deposited in joints causing gout and in kidney tubules inducing nephrolithiasis. In mice, plasma urate levels are controlled by hepatic breakdown, as well as, by incompletely understood renal processes of reabsorption and secretion. Here, we investigated the role of the recently identified urate transporter, Glut9, in the physiological control of urate homeostasis using mice with systemic or liver-specific inactivation of the Glut9 gene. We show that Glut9 is expressed in the basolateral membrane of hepatocytes and in both apical and basolateral membranes of the distal nephron. Mice with systemic knockout of Glut9 display moderate hyperuricemia, massive hyperuricosuria, and an early-onset nephropathy, characterized by obstructive lithiasis, tubulointerstitial inflammation, and progressive inflammatory fibrosis of the cortex, as well as, mild renal insufficiency. In contrast, liver-specific inactivation of the Glut9 gene in adult mice leads to severe hyperuricemia and hyperuricosuria, in the absence of urate nephropathy or any structural abnormality of the kidney. Together, our data show that Glut9 plays a major role in urate homeostasis by its dual role in urate handling in the kidney and uptake in the liver.gout ͉ knockout ͉ nephrolithiasis ͉ uric acid

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

Cited by 216 publications

References 68 publications

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

Uric acid transport and disease

Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy

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