Fibroblast growth factor 23 leads to endolysosomal routing of the renal phosphate cotransporters NaPi-IIa and NaPi-IIc in vivo

Küng, Catharina J.; Haykir, Betül; Schnitzbauer, Udo; Egli-Spichtig, Daniela; Hernando, Nati; Wagner, Carsten A.

doi:10.1152/ajprenal.00250.2021

Cited by 18 publications

(11 citation statements)

References 57 publications

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“…In humans and animal models, Pi intake rapidly triggers an increase in PTH followed by a later rise in FGF23 11,15,16 . Both PTH and FGF23 can trigger internalization and downregulation of NaPi‐IIa, NaPi‐IIc, and Pit2 Pi transporters albeit with different temporal dynamics 9,17,18 . Elevated PTH induces phosphaturia in Pi‐gavaged rats, 11 while the role of FGF23 in the acute response to Pi intake has been less well defined.…”

Section: Introductionmentioning

confidence: 99%

“…11,15,16 Both PTH and FGF23 can trigger internalization and downregulation of NaPi-IIa, NaPi-IIc, and Pit2 Pi transporters albeit with different temporal dynamics. 9,17,18 Elevated PTH induces phosphaturia in Pi-gavaged rats, 11 while the role of FGF23 in the acute response to Pi intake has been less well defined. PTH and FGF23 are linked through several regulatory loops by which PTH stimulates 1,25-(OH) 2 vitamin D 3 levels which enhance FGF23 production and levels.…”

Section: Introductionmentioning

confidence: 99%

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Acute adaptation of renal phosphate transporters in the murine kidney to oral phosphate intake requires multiple signals

et al. 2022

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Aims Dietary inorganic phosphate (Pi) modulates renal Pi reabsorption by regulating the expression of the NaPi‐IIa and NaPi‐IIc Pi transporters. Here, we aimed to clarify the role of several Pi‐regulatory mechanisms including parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) and inositol hexakisphosphate kinases (IP6‐kinases) in the acute regulation of NaPi‐IIa and NaPi‐IIc. Methods Wildtype (WT) and PTH‐deficient mice (PTH‐KO) with/without inhibition of FGF23 signalling were gavaged with Pi/saline and examined at 1, 4 and 12 h. Results Pi‐gavage elevated plasma Pi and decreased plasma Ca2+ in both genotypes after 1 h Within 1 h, Pi‐gavage decreased NaPi‐IIa abundance in WT and PTH‐KO mice. NaPi‐IIc was downregulated 1 h post‐administration in WT and after 4 h in PTH‐KO. PTH increased after 1 h in WT animals. After 4 h Pi‐gavage, FGF23 increased in both genotypes being higher in the KO group. PTHrp and dopamine were not altered by Pi‐gavage. Blocking FGF23 signalling blunted PTH upregulation in WT mice and reduced NaPi‐IIa downregulation in PTH‐KO mice 4 h after Pi‐gavage. Inhibition of IP6‐kinases had no effect. Conclusions (1) Acute downregulation of renal Pi transporters in response to Pi intake occurs also in the absence of PTH and FGF23 signalling, (2) when FGF23 signalling is blocked, a partial contribution of PTH is revealed, (3) IP6 kinases, intracellular Pi‐sensors in yeast and bacteria, are not involved, and (4) Acute Pi does not alter PTHrp and dopamine. Thus, signals other than PTH, PTHrp, FGF23 and dopamine contribute to renal adaption.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acute adaptation of renal phosphate transporters in the murine kidney to oral phosphate intake requires multiple signals

et al. 2022

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“…Fibroblast growth factor 23 (FGF23) is a hormone synthesized by bone cells that regulates the 'bone-kidney' axis and calcium phosphate metabolism (40)(41)(42). FGF23 reduces serum phosphate levels by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption (43), while also reducing plasma calcitriol levels by down-regulating the expression of the renal 1-a hydroxylase and up-regulates 24-hydroxylase (44). These mechanisms explain the hypophosphatemia effect of FGF23.…”

Section: Effect Of Gc On Fibroblast Growth Factor 23 (Fgf23)mentioning

confidence: 99%

Glucocorticoid induced bone disorders in children: Research progress in treatment mechanisms

Hua

Huang

et al. 2023

Front. Endocrinol.

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Long-term or supra-physiological dose of glucocorticoid (GC) application in clinic can lead to impaired bone growth and osteoporosis. The side effects of GC on the skeletal system are particularly serious in growing children, potentially causing growth retardation or even osteoporotic fractures. Children’s bone growth is dependent on endochondral ossification of growth plate chondrocytes, and excessive GC can hinder the development of growth plate and longitudinal bone growth. Despite the availability of drugs for treating osteoporosis, they have failed to effectively prevent or treat longitudinal bone growth and development disorders caused by GCs. As of now, there is no specific drug to mitigate these severe side effects. Traditional Chinese Medicine shows potential as an alternative to the current treatments by eliminating the side effects of GC. In summary, this article comprehensively reviews the research frontiers concerning growth and development disorders resulting from supra-physiological levels of GC and discusses the future research and treatment directions for optimizing steroid therapy. This article may also provide theoretical and experimental insight into the research and development of novel drugs to prevent GC-related side effects.

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“…Additional recently published findings include the demonstration that FGF23 decreases apical membrane NPT2A expression by stimulating endocytosis of NPT2A into an endolysosomal pathway [23], a mechanism that had been suspected but not explicitly demonstrated. Lucea et al [24] appear to have settled a longstanding debate about the inhibitory effects of NAD+ on phosphate transport, demonstrating that only after degradation was NAD+ able to inhibit phosphate transport in a cell culture model, and identifying the increase in local phosphate release and the breakdown product ADP-ribose as the responsible agents [24].…”

Section: Regulation Of Expression Of Phosphate Transportersmentioning

confidence: 99%

Understanding renal phosphate handling: unfinished business

Lederer

2023

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewThe purpose of this review is to highlight the publications from the prior 12--18 months that have contributed significant advances in the field of renal phosphate handling. Recent findingsThe discoveries include new mechanisms for the trafficking and expression of the sodium phosphate cotransporters; direct link between phosphate uptake and intracellular metabolic pathways; interdependence between proximal tubule transporters; and the persistent renal expression of phosphate transporters in chronic kidney disease. SummaryDiscovery of new mechanisms for trafficking and regulation of expression of phosphate transporters suggest new targets for the therapy of disorders of phosphate homeostasis. Demonstration of stimulation of glycolysis by phosphate transported into a proximal tubule cell expands the scope of function for the type IIa sodium phosphate transporter from merely a mechanism to reclaim filtered phosphate to a regulator of cell metabolism. This observation opens the door to new therapies for preserving kidney function through alteration in transport. The evidence for persistence of active renal phosphate transport even with chronic kidney disease upends our assumptions of how expression of these transporters is regulated, suggests the possibility of alternative functions for the transporters, and raises the possibility of new therapies for phosphate retention.

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Fibroblast growth factor 23 leads to endolysosomal routing of the renal phosphate cotransporters NaPi-IIa and NaPi-IIc in vivo

Cited by 18 publications

References 57 publications

Acute adaptation of renal phosphate transporters in the murine kidney to oral phosphate intake requires multiple signals

Acute adaptation of renal phosphate transporters in the murine kidney to oral phosphate intake requires multiple signals

Glucocorticoid induced bone disorders in children: Research progress in treatment mechanisms

Understanding renal phosphate handling: unfinished business

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