Npt2 gene disruption confers resistance to the inhibitory action of parathyroid hormone on renal sodium-phosphate cotransport

PTH inhibition of renal sodium-phosphate (Na-Pi) cotransport is associated with the endocytic retrieval of the type II Na-Pi cotransporter, Npt2, from the renal brush border membrane into the late endosomal/lysosomal compartm ent. The aim of the present study was to determine whether mice homozygous for the disrupted Npt2 gene (Npt2(-/-)) exhibit decreased renal Pi reabsorp tion in response to PTH. We demonstrate that PTH has no effect on the serum Pi concentration, fractional excretion of Pi, or Na-dependent Pi transport in renal brush border membrane vesicles in Npt2(-/-) mice. In contrast, PT H elicits a fall in the serum Pi concentration, an increase in urinary Pi e xcretion, a decrease in brush border membrane Na-Pi cotransport, and a corr esponding reduction in the relative abundance of Npt2 protein in wild-type mice (Npt2(+/+)). Both Npt2(-/-) and Npt2(+/+) mice exhibit a significant r ise in the urinary cAMP/creatinine ratio in response to PTH, indicating tha t generalized resistance to PTH cannot account for the absence of the PTH r esponse in Npt2(-/-) mice. In addition, we demonstrate that Pi-depleted nor mal mice respond to PTH with a decrease in renal brush border membrane Na-P i cotransport and Npt2 protein, indicating that Pi deficiency per se does n ot account for PTH resistance in Npt2(-/-) mice. Taken together, our data p rovide compelling evidence that Npt2 gene expression is crucial for PTH eff ects on renal Pi handling.