Activation of a Non-cAMP/PKA Signaling Pathway Downstream of the PTH/PTHrP Receptor Is Essential for a Sustained Hypophosphatemic Response to PTH Infusion in Male Mice

• Published in: Endocrinology (Philadelphia) 2013-05, Vol.154 (5), p.1680-1689
• Main Authors: Guo, Jun, Song, Lige, Liu, Minlin, Segawa, Hiroko, Miyamoto, Ken-Ichi, Bringhurst, F. Richard, Kronenberg, Henry M, Jüppner, Harald
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Biological and medical sciences; Blood; Calcitriol; Calcium (blood); Calcium homeostasis; Calcium ions; Calcium signalling; Calcium-Regulating Hormones; Cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Excretion; Fibroblast growth factor 23; Fibroblasts; Fundamental and applied biological sciences. Psychology; Growth factors; Homeostasis; Hypophosphatemia; Hypophosphatemia - chemically induced; Hypophosphatemia - genetics; Hypophosphatemia - metabolism; Infusions, Intravenous; Kinases; Long-term effects; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation - physiology; Parathyroid hormone; Parathyroid Hormone - administration & dosage; Parathyroid Hormone - adverse effects; Parathyroid Hormone - metabolism; Parathyroid hormone-related protein; Phospholipase C; Protein kinase A; Protein transport; Receptor, Parathyroid Hormone, Type 1 - genetics; Receptor, Parathyroid Hormone, Type 1 - metabolism; Receptor, Parathyroid Hormone, Type 1 - physiology; Receptors; Renal function; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Sodium-Phosphate Cotransporter Proteins, Type IIa - genetics; Sodium-Phosphate Cotransporter Proteins, Type IIa - metabolism; Sodium-Phosphate Cotransporter Proteins, Type IIc - genetics; Sodium-Phosphate Cotransporter Proteins, Type IIc - metabolism; Vertebrates: endocrinology; Vitamin D3
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2012-2240

PTH increases urinary Pi excretion by reducing expression of two renal cotransporters [NaPi-IIa (Npt2a) and NaPi-IIc (Npt2c)]. In contrast to acute transporter regulation that is cAMP/protein kinase A dependent, long-term effects require phospholipase C (PLC) signaling by the PTH/PTHrP receptor (PPR). To determine whether the latter pathway regulates Pi through Npt2a and/or Npt2c, wild-type mice (Wt) and animals expressing a mutant PPR incapable of PLC activation (DD) were tested in the absence of one (Npt2a−/− or Npt2c−/−) or both phosphate transporters (2a/2c-dko). PTH infusion for 8 days caused a rapid and persistent decrease in serum Pi in Wt mice, whereas serum Pi in DD mice fell only transiently for the first 2 days. Consistent with these findings, fractional Pi excretion index was increased initially in both animals, but this increase persisted only when the PPR Wt was present. The hypophosphatemic response to PTH infusion was impaired only slightly in PPR Wt/Npt2c−/− or DD/Npt2c−/− mice. Despite lower baselines, PTH infusion in PPR Wt/Npt2a−/− mice decreased serum Pi further, an effect that was attenuated in DD/Npt2a−/− mice. Continuous PTH had no effect on serum Pi in 2a/2c-dko mice. PTH administration increased serum 1,25 dihydroxyvitamin D3 levels in Wt and DD mice and increased levels above the elevated baseline with ablation of either but not of both transporters. Continuous PTH elevated serum fibroblast growth factor 23 and blood Ca2+ equivalently in all groups of mice. Our data indicate that PLC signaling at the PPR contributes to the long-term effect of PTH on Pi homeostasis but not to the regulation of 1,25 dihydroxyvitamin D3, fibroblast growth factor 23, or blood Ca2+.