TY - JOUR
T1 - Altered renal FGF23-mediated activity involving MAPK and Wnt
T2 - Effects of the Hyp mutation
AU - Farrow, Emily G.
AU - Summers, Lelia J.
AU - Schiavi, Susan C.
AU - McCormick, James A.
AU - Ellison, David H.
AU - White, Kenneth E.
PY - 2010/10
Y1 - 2010/10
N2 - Fibroblast growth factor-23 (FGF23), a hormone central to renal phosphate handling, is elevated in multiple hypophosphatemic disorders. Initial FGF23-dependent Erk1/2 activity in the kidney localizes to the distal convoluted tubule (DCT) with the co-receptor α-Klotho (KL), distinct from Npt2a in proximal tubules (PT). The Hyp mouse model of X-linked hypophosphatemic rickets (XLH) is characterized by hypophosphatemia with increased Fgf23, and patients with XLH elevate FGF23 following combination therapy of phosphate and calcitriol. The molecular signaling underlying renal FGF23 activity, and whether these pathways are altered in hypophosphatemic disorders, is unknown. To examine Npt2a in vivo, mice were injected with FGF23. Initial p-Erk1/2 activity in the DCT occurred within 10 min; however, Npt2a protein was latently reduced in the PT at 30-60 min, and was independent of Npt2a mRNA changes. KL-null mice had no DCT p-Erk1/2 staining following FGF23 delivery. Under basal conditions in Hyp mice, c-Fos and Egr1, markers of renal Fgf23 activity, were increased; however, KL mRNA was reduced 60% (P<0.05). Despite the prevailing hypophosphatemia and elevated Fgf23, FGF23 injections into Hyp mice activated p-Erk1/2 in the DCT. FGF23 injection also resulted in phospho-β-catenin (p-β-cat) co-localization with KL in wild-type mice, and Hyp mice demonstrated strong p-β-cat staining under basal conditions, indicating potential crosstalk between mitogen-activated protein kinase and Wnt signaling. Collectively, these studies refine the mechanisms for FGF23 bioactivity, and demonstrate novel suppression of Wnt signaling in a KL-dependent DCT-PT axis, which is likely altered in XLH. Finally, the current treatment of phosphate and calcitriol for hypophosphatemic disorders may increase FGF23 activity.
AB - Fibroblast growth factor-23 (FGF23), a hormone central to renal phosphate handling, is elevated in multiple hypophosphatemic disorders. Initial FGF23-dependent Erk1/2 activity in the kidney localizes to the distal convoluted tubule (DCT) with the co-receptor α-Klotho (KL), distinct from Npt2a in proximal tubules (PT). The Hyp mouse model of X-linked hypophosphatemic rickets (XLH) is characterized by hypophosphatemia with increased Fgf23, and patients with XLH elevate FGF23 following combination therapy of phosphate and calcitriol. The molecular signaling underlying renal FGF23 activity, and whether these pathways are altered in hypophosphatemic disorders, is unknown. To examine Npt2a in vivo, mice were injected with FGF23. Initial p-Erk1/2 activity in the DCT occurred within 10 min; however, Npt2a protein was latently reduced in the PT at 30-60 min, and was independent of Npt2a mRNA changes. KL-null mice had no DCT p-Erk1/2 staining following FGF23 delivery. Under basal conditions in Hyp mice, c-Fos and Egr1, markers of renal Fgf23 activity, were increased; however, KL mRNA was reduced 60% (P<0.05). Despite the prevailing hypophosphatemia and elevated Fgf23, FGF23 injections into Hyp mice activated p-Erk1/2 in the DCT. FGF23 injection also resulted in phospho-β-catenin (p-β-cat) co-localization with KL in wild-type mice, and Hyp mice demonstrated strong p-β-cat staining under basal conditions, indicating potential crosstalk between mitogen-activated protein kinase and Wnt signaling. Collectively, these studies refine the mechanisms for FGF23 bioactivity, and demonstrate novel suppression of Wnt signaling in a KL-dependent DCT-PT axis, which is likely altered in XLH. Finally, the current treatment of phosphate and calcitriol for hypophosphatemic disorders may increase FGF23 activity.
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U2 - 10.1677/JOE-10-0181
DO - 10.1677/JOE-10-0181
M3 - Article
C2 - 20675303
AN - SCOPUS:77957107138
SN - 0022-0795
VL - 207
SP - 67
EP - 75
JO - Journal of Endocrinology
JF - Journal of Endocrinology
IS - 1
ER -