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Sodium-Hydrogen Exchanger Regulatory Factor-1 Interacts with Mouse Urate Transporter 1 to Regulate Renal Proximal Tubule Uric Acid Transport

Rochelle Cunningham^*, Marc Brazie^*, Srilatha Kanumuru, Xiaofei E^*, Rajat Biswas^*, Fengying Wang^*, Deborah Steplock^*, James B. Wade, Naohiko Anzai, Hitoshi Endou, Shirish Shenolikar^|| and Edward J. Weinman^*,,¶

Departments of ^* Medicine and Physiology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Medicine, Good Samaritan Hospital; Department of Pharmacology and Toxicology, Kyorin University School of Medicine; ^|| Pfizer Global Research and Development; and ^¶ Medical Service, Department of Veterans Affairs Medical Center

Address correspondence to: Dr Rochelle M. Cunningham, University of Maryland School of Medicine, 22 S. Greene St., N3W143, Baltimore, MD 21201. Phone: 410-328-5720; Fax: 410-328-2668; E-mail: rcunning{at}medicine.umaryland.edu

Received for publication September 8, 2006. Accepted for publication February 13, 2007.

Sodium-hydrogen exchanger regulatory factor-1–deficient (NHERF-1^–/–) mice demonstrate increases in the urinary excretion of phosphate, calcium, and uric acid associated with interstitial deposition of calcium in the papilla of the kidney. These studies examine the role of NHERF-1 in the tubular reabsorption of uric acid and regulation of mouse urate transporter 1 (mURAT1), a newly described transporter that is responsible for the renal tubular reabsorption of uric acid. In primary cultures of mouse renal proximal tubule cells, uric acid uptake was significantly lower in NHERF-1^–/– cells compared with wild-type cells over a large range of uric acid concentrations in the media. Western immunoblotting revealed a 56 ± 6% decrease in the brush border membrane (BBM) expression of mURAT1 in NHERF-1^–/– compared with wild-type control kidneys (P < 0.05). Confocal microscopy confirmed the reduced apical membrane expression of mURAT1 in NHERF-1^–/– kidneys and demonstrated mislocalization of mURAT1 to intracellular vesicular structures. Para-aminohippurate significantly inhibited uric acid uptake in wild-type cells (41 ± 2%) compared with NHERF-1^–/– cells (8.2 ± 3%). Infection of NHERF-1^–/– cells with adenovirus–green fluorescence protein–NHERF-1 resulted in significantly higher rates of uric acid transport (15.4 ± 1.1 pmol/µg protein per 30 min) compared with null cells that were infected with control adenovirus–green fluorescence protein (7.9 ± 0.3) and restoration of the inhibitory effect of para-aminohippurate (% inhibition 34 ± 4%). These findings indicate that NHERF-1 exerts a significant effect on the renal tubular reabsorption of uric acid in the mouse by modulating the BBM abundance of mURAT1 and possibly other BBM uric acid transporters.

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