Ablation of the Stimulatory G Protein α-Subunit in Renal Proximal Tubules Leads to Parathyroid Hormone-Resistance With Increased Renal Cyp24a1 mRNA Abundance and Reduced Serum 1,25-Dihydroxyvitamin D

Endocrinology. 2016 Feb;157(2):497-507. doi: 10.1210/en.2015-1639. Epub 2015 Dec 15.

Abstract

PTH regulates serum calcium, phosphate, and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels by acting on bone and kidney. In renal proximal tubules (PTs), PTH inhibits reabsorption of phosphate and stimulates the synthesis of 1,25(OH)2D. The PTH receptor couples to multiple G proteins. We here ablated the α-subunit of the stimulatory G protein (Gsα) in mouse PTs by using Cre recombinase driven by the promoter of type-2 sodium-glucose cotransporter (Gsα(Sglt2KO) mice). Gsα(Sglt2KO) mice were normophosphatemic but displayed, relative to controls, hypocalcemia (1.19 ±0.01 vs 1.23 ±0.01 mmol/L; P < .05), reduced serum 1,25(OH)2D (59.3 ±7.0 vs 102.5 ±12.2 pmol/L; P < .05), and elevated serum PTH (834 ±133 vs 438 ±59 pg/mL; P < .05). PTH-induced elevation in urinary cAMP excretion was blunted in Gsα(Sglt2KO) mice (2- vs 4-fold over baseline in controls; P < .05). Relative to baseline in controls, PTH-induced reduction in serum phosphate tended to be blunted in Gsα(Sglt2KO) mice (-0.39 ±0.33 vs -1.34 ±0.36 mg/dL; P = .07). Gsα(Sglt2KO) mice showed elevated renal vitamin D 24-hydroxylase and bone fibroblast growth factor-23 (FGF23) mRNA abundance (∼3.4- and ∼11-fold over controls, respectively; P < .05) and tended to have elevated serum FGF23 (829 ±76 vs 632 ±60 pg/mL in controls; P = .07). Heterozygous mice having constitutive ablation of the maternal Gsα allele (E1(m-/+)) (model of pseudohypoparathyroidism type-Ia), in which Gsα levels in PT are reduced, also exhibited elevated serum FGF23 (474 ±20 vs 374 ±27 pg/mL in controls; P < .05). Our findings indicate that Gsα is required in PTs for suppressing renal vitamin D 24-hydroxylase mRNA levels and for maintaining normal serum 1,25(OH)2D.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Down-Regulation / genetics
  • Drug Resistance / genetics*
  • Female
  • GTP-Binding Protein alpha Subunits / genetics*
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Parathyroid Hormone / metabolism
  • Parathyroid Hormone / pharmacology*
  • Pseudopseudohypoparathyroidism / genetics*
  • Pseudopseudohypoparathyroidism / pathology
  • RNA, Messenger / metabolism
  • Up-Regulation / genetics
  • Vitamin D / analogs & derivatives*
  • Vitamin D / blood
  • Vitamin D3 24-Hydroxylase / genetics*
  • Vitamin D3 24-Hydroxylase / metabolism

Substances

  • GTP-Binding Protein alpha Subunits
  • Parathyroid Hormone
  • RNA, Messenger
  • Vitamin D
  • 1,25-dihydroxyvitamin D
  • Cyp24a1 protein, mouse
  • Vitamin D3 24-Hydroxylase