Abstract
Fibroblast growth factor-23 (FGF23), a hormone central to phosphate and vitamin D metabolism, reduces renal absorption of phosphate by downregulating the sodium-phosphate cotransporter Npt2a. However, the mechanisms of FGF23 action in the kidney are unclear, as Npt2a localizes to the proximal tubule (PT) and the FGF23 coreceptor alpha-Klotho (KL) localizes to the distal convoluted tubule (DCT). Immunofluorescent analyses following FGF23 injection in mice showed robust staining for phospho-ERK1/2, a marker of FGF23 bioactivity, only within the DCT in a subset of KL-positive cells. This activity colocalized with the FGF23 receptor FGFR1 and was present in DCT cells that were adjacent to Npt2a-expressing PT segments. Although KL is expressed as both secreted and membrane-bound isoforms, only the membrane-bound isoform was capable of mediating FGF23 bioactivity. These findings provide novel insight into the mechanisms of hormone-regulated phosphate metabolism by identifying an intrarenal signaling axis for FGF23.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Animals
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Cell Line
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DNA Primers
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Early Growth Response Protein 1 / genetics
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Fibroblast Growth Factor-23
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Fibroblast Growth Factors / pharmacology
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Fibroblast Growth Factors / physiology*
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Glucuronidase / physiology
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Humans
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Kidney
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Kidney Tubules, Distal / enzymology
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Kidney Tubules, Distal / physiology*
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Klotho Proteins
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Mice
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Mice, Inbred C57BL
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Receptor, Fibroblast Growth Factor, Type 1 / genetics
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Receptor, Fibroblast Growth Factor, Type 1 / metabolism
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Recombinant Proteins / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / physiology
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Sodium-Phosphate Cotransporter Proteins / physiology*
Substances
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Actins
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DNA Primers
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EGR1 protein, human
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Early Growth Response Protein 1
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FGF23 protein, human
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Fgf23 protein, mouse
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Recombinant Proteins
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Sodium-Phosphate Cotransporter Proteins
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Fibroblast Growth Factors
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Fibroblast Growth Factor-23
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Receptor, Fibroblast Growth Factor, Type 1
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Glucuronidase
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Klotho Proteins