Human Sodium Phosphate Transporter 4 (hNPT4/SLC17A3) as a Common Renal Secretory Pathway for Drugs and Urate

Abstract

The evolutionary loss of hepatic urate oxidase (uricase) has resulted in humans with elevated serum uric acid (urate). Uricase loss may have been beneficial to early primate survival. However, an elevated serum urate has predisposed man to hyperuricemia, a metabolic disturbance leading to gout, hypertension, and various cardiovascular diseases. Human serum urate levels are largely determined by urate reabsorption and secretion in the kidney. Renal urate reabsorption is controlled via two proximal tubular urate transporters: apical URAT1 (SLC22A12) and basolateral URATv1/GLUT9 (SLC2A9). In contrast, the molecular mechanism(s) for renal urate secretion remain unknown. In this report, we demonstrate that an orphan transporter hNPT4 (human sodium phosphate transporter 4; SLC17A3) was a multispecific organic anion efflux transporter expressed in the kidneys and liver. hNPT4 was localized at the apical side of renal tubules and functioned as a voltage-driven urate transporter. Furthermore, loop diuretics, such as furosemide and bumetanide, substantially interacted with hNPT4. Thus, this protein is likely to act as a common secretion route for both drugs and may play an important role in diuretics-induced hyperuricemia. The in vivo role of hNPT4 was suggested by two hyperuricemia patients with missense mutations in SLC17A3. These mutated versions of hNPT4 exhibited reduced urate efflux when they were expressed in Xenopus oocytes. Our findings will complete a model of urate secretion in the renal tubular cell, where intracellular urate taken up via OAT1 and/or OAT3 from the blood exits from the cell into the lumen via hNPT4.Urate is the end product of purine metabolism in humans and certain primates as a result of uricase genetic loss (urate oxidase degrades urate to allantoin) (1). Two independent nonsense mutations in this gene, found in human, chimpanzee, and orangutan but not in the gibbon, indicate that this loss had evolutionary advantages for early primates (2). Because urate has powerful antioxidant properties, uricase loss resulting in elevated serum urate may have been beneficial to early primate survival (1). In addition, Watanabe et al. (3) hypothesized that elevated serum urate levels provided a survival advantage by helping to maintain blood pressure under the low salt dietary conditions that prevailed during the middle to late Miocene period. Despite its beneficial role and given the fact that more than half of uricase-deficient mice die from urate nephropathy within 4 weeks of age, elevation in serum urate level produces a burden on the body (4). To circumvent this problem, the human body had to develop a urate excretion system.The kidney plays a dominant role in maintaining serum urate levels (1, 5). Renal urate excretion is a function of the balance between reabsorption and secretion. Recently it was demonstrated that luminal urate is taken up by a urate-anion exchanger (URAT1; SLC22A12) 3 (6) into the renal proximal tubular cell and that intracellular urate exits the cell into the interstitium/blood ...

Clinical Consequences of Mutations in Sodium Phosphate Cotransporters

“…Several studies have demonstrated an association between Npt4 single nucleotide polymorphisms and uric acid concentration in the serum and gout (17)(18)(19)(20). Npt4 interacts with diuretics such as furosemide and bumetanide, suggesting that it may be responsible for the renal proximal tubule secretion of diuretics (21). Although Npt4 has also been identified in liver cells as a microsomal phosphate transporter (22), Npt4 is not felt to play a significant role in phosphate homeostasis.…”

Everything we always wanted to know about furosemide but were afraid to ask

“…Several mechanisms have been suggested. Furosemide inhibits the human sodium phosphate transporter 4 (hNPT4) in proximal tubules, which releases urate into the tubular lumen (76). Moreover, hyperuricemia often coexists with hypertension, CKD, and cardiovascular disease (CVD).…”

Uric acid transporters hiding in the intestine

“…Human sodium phosphate transporter 4 (hNPT4) is localized at the apical side of renal tubules and functions as a voltage-driven uric acid transporter. It is likely to act as a common secretion route for both drugs and may play an important role in diuretics-induced hyperuricaemia (Jutabha et al 2010). Actually, NPT4 is present in the small intestine too (Reimer & Edwards 2004).…”