Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b+/- mice

Ohi A, Hanabusa E, Ueda O, Segawa H, Horiba N, Kaneko I, Kuwahara S, Mukai T, Sasaki S, Tominaga R, Furutani J, Aranami F, Ohtomo S, Oikawa Y, Kawase Y, Wada NA, Tachibe T, Kakefuda M, Tateishi H, Matsumoto K, Tatsumi S, Kido S, Fukushima N, Jishage K, Miyamoto K. Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b(+/-) mice. Am J Physiol Renal Physiol 301: F1105-F1113, 2011. First published August 3, 2011; doi:10.1152/ajprenal.00663.2010.-An inorganic phosphate (P-i)-restricted diet is important for patients with chronic kidney disease and patients on hemodialysis. Phosphate binders are essential for preventing hyperphosphatemia and ectopic calcification. The sodium-dependent P-i (Na/P-i) transport system is involved in intestinal P-i absorption and is regulated by several factors. The type II sodium-dependent P-i transporter Npt2b is expressed in the brush-border membrane in intestinal epithelial cells and transports P-i. In the present study, we analyzed the phenotype of Npt2b(-/-) and hetero(+/-) mice. Npt2b(-/-) mice died in utero soon after implantation, indicating that Npt2b is essential for early embryonic development. At 4 wk of age, Npt2b(+/-) mice showed hypophosphatemia and low urinary P-i excretion. Plasma fibroblast growth factor 23 levels were significantly decreased and 1,25(OH)(2)D-3 levels were significantly increased in Npt2b(+/-) mice compared with Npt2b(+/+) mice. Npt2b mRNA levels were reduced to 50% that in Npt2b(+/+) mice. In contrast, renal Npt2a and Npt2c transporter protein levels were significantly increased in Npt2b(+/-) mice. At 20 wk of age, Npt2b(+/-) mice showed hypophosphaturia and reduced Na/P-i cotransport activity in the distal intestine. Npt2b(+/+) mice with adenine-induced renal failure had hyperphosphatemia and high plasma creatinine levels. Npt2b(+/-) mice treated with adenine had significantly reduced plasma Pi levels compared with Npt2b(+/+) mice. Intestinal Npt2b protein and Na+/P-i transport activity levels were significantly lower in Npt2b(+/-) mice than in the Npt2b(+/+) mice. The findings of the present studies suggest that Npt2b is an important target for the prevention of hyperphosphatemia.