GSK3-controlled sympathetic activity in FGF23 production and FGF23 gene regulation by actin cytoskeleton reorganization

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dc.contributor.advisor Lang, Florian (Prof. Dr.)
dc.contributor.author Fajol, Abul
dc.date.accessioned 2016-02-18T09:08:24Z
dc.date.available 2016-02-18T09:08:24Z
dc.date.issued 2016
dc.identifier.other 455626030 de_DE
dc.identifier.uri http://hdl.handle.net/10900/68433
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-684332 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-9852
dc.description.abstract Fibroblast growth factor (FGF) 23 is a bone derived phosphaturic hormone. It is a potent regulator of vitamin D metabolism and phosphate homeostasis. FGF23 is secreted from the bone and exerts its function on the kidney. Further, it inhibits 25-dihydroxyvitamin D 1α-hydroxylase and reduces formation of active vitamin D and stimulates 25-dihydroxyvitamin D 24-hydroxylase, which in turn favors degradation of vitamin D. FGF23 inhibits renal phosphate reabsorption in the proximal tubules, thereby lowering serum phosphate and active vitamin D. To exert its renal function, FGF23 requires klotho as a co-receptor. Both FGF23 and klotho deficiency, lead to vascular calcification, hyperphosphatemia, hypercalcemia, muscular atrophy and profound aging like phenotypes. Glycogen synthase kinase (GSK) 3 is a serine-threonine kinase, which is ubiquitously expressed and involved in a variety of cellular process including; glycogen metabolism, transcription, translation, proliferation, survival, cell cycle regulation, cytoskeleton reorganization and apoptosis. GSK3 is a downstream signaling molecule of phosphoinositide-3 kinase (PI3 kinase)/PKB/Akt pathway. Mice expressing PKB insensitive GSK3α/β (gsk-3ki) show enhanced sympathetic nervous activity and phosphaturia with low bone density. The sympathetic nervous system was shown to stimulate FGF23 release. In this thesis, I investigated the role of GSK3-controlled sympathetic activity in the production of FGF23 and phosphate metabolism. Serum FGF23, urinary epinephrine, Vanillylmandelic acid (VMA), phosphate and calcium excretion were significantly higher in gsk-3ki mice compared to gsk-3WT mice. Serum FGF23 and 1,25(OH)2D3 concentrations were lower in gsk3KI mice than in gsk-3WT mice. Mice were treated with β-blocker (propranolol) for one week resulted in decreased serum FGF23 and renal phosphate and calcium loss and elevated serum phosphate concentration in gsk-3KI mice. Thus, these data suggest that PI3K insensitive GSK3 participates in the regulation of FGF23 formation, vitamin D metabolism and, thereby mineral metabolism by sympathetic nervous system. Next, I explored the role of actin cytoskeleton reorganization in controlling FGF23 production. Previous findings have suggested that 1,25(OH)2D3 and NF-κB stimulates FGF23 production. Therefore, the role of 1,25(OH)2D3-induced actin polymerization on Fgf23 expression in UMR 106 osteoblast-like cells was explored. Actin polymerization dynamics was determined by Western blotting and confocal imaging and Fgf23 transcript levels was measured by qRT-PCR. Western blotting and confocal imaging data showed 1,25(OH)2D3 induces actin polymerization in UMR 106 osteoblast-like cells. Thus induction of FGF23 production by 1,25(OH)2D3 resulted in actin polymerization, an effect blocked by the pharmacological inhibitor of NF-κB wogonin (100 μM). Cytochalasin B (100 nM) is a actin microfilament disrupting agent which abolished 1,25(OH)2D3-induced Fgf23 gene transcription, pointing a role of actin cytoskeleton in Fgf23 expression. Both Rac1 inhibitor NSC23766 (50 μM) and IPA3 (10 μM) blocked 1,25(OH)2D3-induced Fgf23 expression, suggesting the mechanism involved in actin cytoskeleton- controlled Fgf23 expression in UMR 106 cells involves Rac1 small GTPase signaling. These results provide strong evidence that actin reorganization regulated by Rac1 signaling contributes to 1,25(OH)2D3-induced Fgf23 gene transcription. de_DE
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en en
dc.subject.classification Gen , Hormon , Zellskelett , Actin de_DE
dc.subject.ddc 570 de_DE
dc.subject.other FGF23 en
dc.subject.other cytoskeleton en
dc.title GSK3-controlled sympathetic activity in FGF23 production and FGF23 gene regulation by actin cytoskeleton reorganization en
dc.type Dissertation de_DE
dcterms.dateAccepted 2016-02-08
utue.publikation.fachbereich Biologie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE

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