Enhanced FGF23 production in mice expressing PI3K-insensitive GSK3 is normalized by β-blocker treatment.

Abstract

Glycogen synthase kinase (GSK)-3 is a ubiquitously expressed kinase inhibited by insulin-dependent Akt/PKB/SGK. Mice expressing Akt/PKB/SGK-resistant GSK3α/GSK3β (gsk3(KI)) exhibit enhanced sympathetic nervous activity and phosphaturia with decreased bone density. Hormones participating in phosphate homeostasis include fibroblast growth factor (FGF)-23, a bone-derived hormone that inhibits 1,25-dihydroxyvitamin D3 (1,25(OH)2D3; calcitriol) formation and phosphate reabsorption in the kidney and counteracts vascular calcification and aging. FGF23 secretion is stimulated by the sympathetic nervous system. We studied the role of GSK3-controlled sympathetic activity in FGF23 production and phosphate metabolism. Serum FGF23, 1,25(OH)2D3, and urinary vanillylmandelic acid (VMA) were measured by ELISA, and serum and urinary phosphate and calcium were measured by photometry in gsk3(KI) and gsk3(WT) mice, before and after 1 wk of oral treatment with the β-blocker propranolol. Urinary VMA excretion, serum FGF23, and renal phosphate and calcium excretion were significantly higher, and serum 1,25(OH)2D3 and phosphate concentrations were lower in gsk3(KI) mice than in gsk3(WT) mice. Propranolol treatment decreased serum FGF23 and loss of renal calcium and phosphate and increased serum phosphate concentration in gsk3(KI) mice. We conclude that Akt/PKB/SGK-sensitive GSK3 inhibition participates in the regulation of FGF23 release, 1,25(OH)2D3 formation, and thus mineral metabolism, by controlling the activity of the sympathetic nervous system.

• Authors: Abul Fajol, Hong Chen, Anja T Umbach, L Darryl Quarles, Florian Lang, Michael Föller
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 30 Issue 2 Pg. 994-1001 (Feb 2016) ISSN: 1530-6860 [Electronic] United States
• PMID: 26527066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• Adrenergic beta-Antagonists
• Fgf23 protein, mouse
• Phosphates
• Vanilmandelic Acid
• Fibroblast Growth Factors
• Fibroblast Growth Factor-23
• Propranolol
• Glycogen Synthase Kinase 3
• Calcitriol
• Calcium

Topics

• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Calcitriol (metabolism)
• Calcium (metabolism)
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (biosynthesis, genetics)
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Kidney (metabolism)
• Mice
• Mice, Mutant Strains
• Phosphates (metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Propranolol (pharmacology)
• Vanilmandelic Acid (pharmacokinetics, pharmacology)