Renal adaptation to phosphate deprivation in the Hyp mouse with X-linked hypophosphatemia

Abstract

The mechanism of renal adaptation to variation in dietary inorganic phosphate (Pi) was investigated in intact Hyp/+ (heterozygous) mice and +/+ (normal homozygous) female siblings. Hyp/+ mice were selected for expression of the X-linked Hyp allele, when fed the control diet (0.6% P), by evidence of persistent postweaning hypophosphatemia (1.78 ± 0.08 mM, mean ± SE, versus 2.68 ± 0.19 mM in +/+ siblings (p < 0.01)). Hyp/+ mice had an elevated fractional excretion index for Pi (FEIPi) (0.570 ± 0.024, mean ± SE) on this diet versus +/+ siblings (0.352 ± 0.025, p < 0.001). Renal cortex content of Pi (~46 nmol/mg protein) and net radioisotopic uptake of Pi by slices were similar in Hyp/+ and +/+ mice. Purified brush border membrane vesicles (BBMV) from Hyp/+ kidney cortex transported labelled Pi (100 μM) by a Na+-dependent mode at about one-half the rate (p < 0.001) observed in +/+ mice. Hyp/+ and +/+ mice fed a low P diet (0.03%) maintained their phenotypic differences in vivo and in vitro. Both adapted to chronic (> 2 week) Pi deprivation with a striking reduction (40- to 50-fold) of FEIPi (p < 0.001) and a fall in plasma [Pi] (p < 0.001). Neither the renal Pi content nor uptake of Pi by slices changed in deprived Hyp/+ and +/+ mice. On the other hand, BBMV uptake by Na+-dependent cotransport increased 200% (p < 0.001) during Pi deprivation in both the Hyp/+ and +/+ mouse. D-glucose transport did not increase. We conclude that renal adaptation to phosphate deprivation is achieved by modulation of a component of Na+-dependent cotransport in brush border membrane that is not controlled by the X-linked gene.