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

Abstract

An inorganic phosphate (Pi)-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 Pi(Na/Pi) transport system is involved in intestinal Piabsorption and is regulated by several factors. The type II sodium-dependent Pitransporter Npt2b is expressed in the brush-border membrane in intestinal epithelial cells and transports Pi. 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 Piexcretion. Plasma fibroblast growth factor 23 levels were significantly decreased and 1,25(OH)2D3levels 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/Picotransport 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 Pilevels compared with Npt2b+/+mice. Intestinal Npt2b protein and Na+/Pitransport 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.