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.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 West Walnut Street, Indianapolis, IN 46202, USA.
Emily G
EG
Farrow
Siobhan I
SI
Davis
Lelia J
LJ
Summers
Kenneth E
KE
White
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