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

Abul Fajol, Hong Chen, Anja T. Umbach, Leigh Quarles, Florian Lang, Michael Föller

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Glycogen synthase kinase (GSK)-3 is a ubiquitously expressed kinase inhibited by insulindependent Akt/PKB/SGK. Mice expressing Akt/PKB/ SGK-resistant GSK3α/GSK3β (gsk3KI) 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 gsk3KI and gsk3WT mice, before and after 1 wk of oral treatment with the b-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 gsk3KI mice than in gsk3WT mice. Propranolol treatment decreased serum FGF23 and loss of renal calcium and phosphate and increased serum phosphate concentration in gsk3KI 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.-Fajol, A., Chen, H., Umbach, A. T., Quarles, L. D., Lang, F., Föller, M. Enhanced FGF23 production in mice expressing PI3Kinsensitive GSK3 is normalized by b-blocker treatment.

Original languageEnglish (US)
Pages (from-to)994-1001
Number of pages8
JournalFASEB Journal
Volume30
Issue number2
DOIs
StatePublished - Feb 1 2016

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Phosphatidylinositol 3-Kinases
Phosphates
Vanilmandelic Acid
Serum
Calcitriol
Neurology
Metabolism
Propranolol
Sympathetic Nervous System
Kidney
Bone
Hormones
Glycogen Synthase Kinase 3
Therapeutics
Photometry
Familial Hypophosphatemia
Vascular Calcification
Minerals
Phosphotransferases
Bone Density

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Enhanced FGF23 production in mice expressing PI3K-insensitive GSK3 is normalized by β-blocker treatment. / Fajol, Abul; Chen, Hong; Umbach, Anja T.; Quarles, Leigh; Lang, Florian; Föller, Michael.

In: FASEB Journal, Vol. 30, No. 2, 01.02.2016, p. 994-1001.

Research output: Contribution to journalArticle

Fajol, Abul ; Chen, Hong ; Umbach, Anja T. ; Quarles, Leigh ; Lang, Florian ; Föller, Michael. / Enhanced FGF23 production in mice expressing PI3K-insensitive GSK3 is normalized by β-blocker treatment. In: FASEB Journal. 2016 ; Vol. 30, No. 2. pp. 994-1001.
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AB - Glycogen synthase kinase (GSK)-3 is a ubiquitously expressed kinase inhibited by insulindependent Akt/PKB/SGK. Mice expressing Akt/PKB/ SGK-resistant GSK3α/GSK3β (gsk3KI) 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 gsk3KI and gsk3WT mice, before and after 1 wk of oral treatment with the b-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 gsk3KI mice than in gsk3WT mice. Propranolol treatment decreased serum FGF23 and loss of renal calcium and phosphate and increased serum phosphate concentration in gsk3KI 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.-Fajol, A., Chen, H., Umbach, A. T., Quarles, L. D., Lang, F., Föller, M. Enhanced FGF23 production in mice expressing PI3Kinsensitive GSK3 is normalized by b-blocker treatment.

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