Initial FGF23-mediated signaling occurs in the distal convoluted tubule.
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.
Farrow
Emily G
EG
Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 West Walnut Street, Indianapolis, IN 46202, USA.
Davis
Siobhan I
SI
Summers
Lelia J
LJ
White
Kenneth E
KE
D000199:Actins / Q000235:genetics; D000818:Animals; D002460:Cell Line; D017931:DNA Primers; D051766:Early Growth Response Protein 1 / Q000235:genetics; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000494:pharmacology / Q000502:physiology*; D005966:Glucuronidase / Q000502:physiology; D006801:Humans; D007668:Kidney; D007686:Kidney Tubules, Distal / Q000201:enzymology / Q000502:physiology*; D000090265:Klotho Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D050608:Sodium-Phosphate Cotransporter Proteins / Q000502:physiology*
D000199:Actins; D017931:DNA Primers; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D011994:Recombinant Proteins; D050608:Sodium-Phosphate Cotransporter Proteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005966:Glucuronidase; D000090265:Klotho Proteins