| First Author | Zhu Y | Year | 2016 |
| Journal | Endocrinology | Volume | 157 |
| Issue | 2 | Pages | 497-507 |
| PubMed ID | 26671181 | Mgi Jnum | J:233851 |
| Mgi Id | MGI:5788219 | Doi | 10.1210/en.2015-1639 |
| Citation | Zhu Y, et al. (2016) Ablation of the Stimulatory G Protein alpha-Subunit in Renal Proximal Tubules Leads to Parathyroid Hormone-Resistance With Increased Renal Cyp24a1 mRNA Abundance and Reduced Serum 1,25-Dihydroxyvitamin D. Endocrinology 157(2):497-507 |
| abstractText | 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 alpha-subunit of the stimulatory G protein (Gsalpha) in mouse PTs by using Cre recombinase driven by the promoter of type-2 sodium-glucose cotransporter (Gsalpha(Sglt2KO) mice). Gsalpha(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 Gsalpha(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 Gsalpha(Sglt2KO) mice (-0.39 +/-0.33 vs -1.34 +/-0.36 mg/dL; P = .07). Gsalpha(Sglt2KO) mice showed elevated renal vitamin D 24-hydroxylase and bone fibroblast growth factor-23 (FGF23) mRNA abundance ( approximately 3.4- and approximately 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 Gsalpha allele (E1(m-/+)) (model of pseudohypoparathyroidism type-Ia), in which Gsalpha 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 Gsalpha is required in PTs for suppressing renal vitamin D 24-hydroxylase mRNA levels and for maintaining normal serum 1,25(OH)2D. |
