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 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.
Zhao
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Department of Pediatrics, McGill University-Montréal Children's Hospital Research Institute, Québec, Canada.
Tenenhouse
H S
HS
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D007668:Kidney / Q000378:metabolism* / Q000648:ultrastructure; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D010710:Phosphates / Q000097:blood / Q000378:metabolism* / Q000652:urine; D012964:Sodium / Q000378:metabolism*; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters
D002352:Carrier Proteins; D010281:Parathyroid Hormone; D010710:Phosphates; C493549:Slc17a2 protein, mouse; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters; D012964:Sodium