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

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 (GsαSglt2KO mice). GsαSglt2KO mice were normophosphatemic but displayed, relative to controls, hypocalcemia (1.19 ±0.01 vs 1.23±0.01 mmol/L; P < .05). PTH-induced elevation in urinary cAMP excretion was blunted in GsαSglt2KO mice (2- vs 4-fold over baseline 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.