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Npt2 Gene Disruption Confers Resistance to the Inhibitory Action of Parathyroid Hormone on Renal Sodium-Phosphate Cotransport¹

Departments of Pediatrics (N.Z., H.S.T.) and Human Genetics (H.S.T.), McGill University-Montréal Children’s Hospital Research Institute, Montréal, Québec, Canada H3H 1P3

Address all correspondence and requests for reprints to: Harriet S. Tenenhouse, Ph.D., Montréal Children’s Hospital, 2300 Tupper Street, Montréal, Québec, Canada H3H 1P3. E-mail: mhdt{at}www.debelle.mcgill.ca

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 compartment. The aim of the present study was to determine whether mice homozygous for the disrupted Npt2 gene (Npt2^-/-) exhibit decreased renal Pi reabsorption 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, PTH elicits a fall in the serum Pi concentration, an increase in urinary Pi excretion, a decrease in brush border membrane Na-Pi cotransport, and a corresponding reduction in the relative abundance of Npt2 protein in wild-type mice (Npt2^+/+). Both Npt2^-/- and Npt2^+/+ mice exhibit a significant rise in the urinary cAMP/creatinine ratio in response to PTH, indicating that generalized resistance to PTH cannot account for the absence of the PTH response in Npt2^-/- mice. In addition, we demonstrate that Pi-depleted normal mice respond to PTH with a decrease in renal brush border membrane Na-Pi cotransport and Npt2 protein, indicating that Pi deficiency per se does not account for PTH resistance in Npt2^-/- mice. Taken together, our data provide compelling evidence that Npt2 gene expression is crucial for PTH effects on renal Pi handling.

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