TY - JOUR
T1 - Differential regulation of renal Klotho and FGFR1 in normal and uremic rats
AU - Muñoz-Castañeda, Juan R.
AU - Herencia, Carmen
AU - Pendón-Ruiz de Mier, Maria Victoria
AU - Rodriguez-Ortiz, Maria Encarnación
AU - Diaz-Tocados, Juan M.
AU - Vergara, Noemi
AU - Martínez-Moreno, Julio M.
AU - Salmerón, Maria Dolores
AU - Richards, William G.
AU - Felsenfeld, Arnold
AU - Kuro-O, Makoto
AU - Almadén, Yolanda
AU - Rodríguez, Mariano
N1 - Funding Information:
The authors thank Ignacio Lopez (Universidad de Córdoba) for criticism of the study and participation in the correction of the manuscript. This work was partially supported by a Spanish government grant from the Programa Nacional I+D+I 2008–2011 and Instituto de Salud Carlos III (ISCIII) Grants PI14/00638 and PI14/00467, cofinancing from European Funds (FEDER), Consejería de Economía, Innovación, Ciencia y Empleo (Grant CVI-7925) from the Junta de Andalucía, Framework Programme 7 Syskid UE Grant FP7-241544, and EUTOX and REDinREN from the ISCIII. N.V. and J.M.D.-T. were supported by Consejería de Economía, Innovación Grant CVI-7925 Ciencia y Empleo from the Junta de Andalucía. M.E.R.-O. is the recipient of a “Sara Borrell” research contract from the ISCIII. Y.A. and J.R.M.-C. are senior researchers supported by the Nicolás Monardes Programme, Consejeria de Salud-SAS (Junta de Andalucia). M.D.S. is supported by a Laboratorios Rubió SA research award. W.G.R. is employed by Amgen, Inc., and M.R. has received honorarium for lectures from Abbott, Amgen, Inc., Fresenius, and Shire. The remaining authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2017/9
Y1 - 2017/9
N2 - In renal failure, hyperphosphatemia occurs despite a marked elevation in serum fibroblast growth factor (FGF)-23. Abnormal regulation of the FGFR1-Klotho receptor complex may cause a resistance to the phosphaturic action of FGF23. The purpose of the present study was to investigate the regulation of renal Klotho and FGF receptor (FEFR)-1 in healthy and uremic rats induced by 5/6 nephrectomy. In normal rats, the infusion of rat recombinant FGF23 enhanced phosphaturia and increased renal FGFR1 expression; however, Klotho expression was reduced. Uremic rats on a high-phosphate (HP) diet presented hyperphosphatemia with marked elevation of FGF23 and an increased fractional excretion of phosphate (P) that was associated with a marked reduction of Klotho expression and an increase in FGFR1. After neutralization of FGF23 by anti-FGF23 administration, phosphaturia was still abundant, Klotho expression remained low, and the FGFR1 level was reduced. These results suggest that the expression of renal Klotho is modulated by phosphaturia, whereas the FGFR1 expression is regulated by FGF23. Calcitriol (CTR) administration prevented a decrease in renal Klotho expression. In HEK293 cells HP produced nuclear translocation of β-catenin, together with a reduction in Klotho. Wnt/β-catenin inhibition with Dkk-1 prevented the P-induced down-regulation of Klotho. The addition of CTR to HP medium was able to recover Klotho expression. In summary, high FGF23 levels increase FGFR1, whereas phosphaturia decreases Klotho expression through the activation of Wnt/β-catenin pathway.
AB - In renal failure, hyperphosphatemia occurs despite a marked elevation in serum fibroblast growth factor (FGF)-23. Abnormal regulation of the FGFR1-Klotho receptor complex may cause a resistance to the phosphaturic action of FGF23. The purpose of the present study was to investigate the regulation of renal Klotho and FGF receptor (FEFR)-1 in healthy and uremic rats induced by 5/6 nephrectomy. In normal rats, the infusion of rat recombinant FGF23 enhanced phosphaturia and increased renal FGFR1 expression; however, Klotho expression was reduced. Uremic rats on a high-phosphate (HP) diet presented hyperphosphatemia with marked elevation of FGF23 and an increased fractional excretion of phosphate (P) that was associated with a marked reduction of Klotho expression and an increase in FGFR1. After neutralization of FGF23 by anti-FGF23 administration, phosphaturia was still abundant, Klotho expression remained low, and the FGFR1 level was reduced. These results suggest that the expression of renal Klotho is modulated by phosphaturia, whereas the FGFR1 expression is regulated by FGF23. Calcitriol (CTR) administration prevented a decrease in renal Klotho expression. In HEK293 cells HP produced nuclear translocation of β-catenin, together with a reduction in Klotho. Wnt/β-catenin inhibition with Dkk-1 prevented the P-induced down-regulation of Klotho. The addition of CTR to HP medium was able to recover Klotho expression. In summary, high FGF23 levels increase FGFR1, whereas phosphaturia decreases Klotho expression through the activation of Wnt/β-catenin pathway.
KW - Chronic kidney disease
KW - FGF23
KW - Mineral metabolism
KW - Phosphaturia
UR - http://www.scopus.com/inward/record.url?scp=85028923004&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85028923004&partnerID=8YFLogxK
U2 - 10.1096/fj.201700006R
DO - 10.1096/fj.201700006R
M3 - Article
C2 - 28515153
AN - SCOPUS:85028923004
SN - 0892-6638
VL - 31
SP - 3858
EP - 3867
JO - FASEB Journal
JF - FASEB Journal
IS - 9
ER -