Muñoz-Castañeda Juan R, Herencia Carmen, Pendón-Ruiz de Mier Maria Victoria, Rodriguez-Ortiz Maria Encarnación, Diaz-Tocados Juan M, Vergara Noemi, Martínez-Moreno Julio M, Salmerón Maria Dolores, Richards William G, Felsenfeld Arnold, Kuro-O Makoto, Almadén Yolanda, Rodríguez Mariano
Instituto Maimónides para la Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.
Unidad de Gestión Clínica (UGC) Nefrología, Hospital Universitario Reina Sofía, Córdoba, Spain.
FASEB J. 2017 Sep;31(9):3858-3867. doi: 10.1096/fj.201700006R. Epub 2017 May 17.
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.-Muñoz-Castañeda, J. R., Herencia, C., Pendón-Ruiz de Mier, M. V., Rodriguez-Ortiz, M. E., Diaz-Tocados, J. M., Vergara, N., Martínez-Moreno, J. M., Salmerón, M. D., Richards, W. G., Felsenfeld, A., Kuro-O, M., Almadén, Y., Rodríguez, M. Differential regulation of renal Klotho and FGFR1 in normal and uremic rats.
在肾衰竭时，尽管血清成纤维细胞生长因子（FGF）-23显著升高，但仍会出现高磷血症。FGFR1-klotho受体复合物的异常调节可能导致对FGF23的排磷作用产生抵抗。本研究的目的是调查在健康大鼠和5/6肾切除诱导的尿毒症大鼠中，肾脏klotho和FGF受体（FGFR）-1的调节情况。在正常大鼠中，输注大鼠重组FGF23可增强尿磷排泄并增加肾脏FGFR1表达；然而，klotho表达降低。高磷（HP）饮食的尿毒症大鼠出现高磷血症，FGF23显著升高，磷排泄分数增加，这与klotho表达显著降低和FGFR1增加有关。给予抗FGF23中和FGF23后，尿磷排泄仍然丰富，klotho表达仍然较低，FGFR1水平降低。这些结果表明，肾脏klotho的表达受尿磷排泄调节，而FGFR1的表达受FGF23调节。给予骨化三醇（CTR）可防止肾脏klotho表达降低。在HEK293细胞中，HP导致β-连环蛋白核转位，同时klotho减少。用Dkk-1抑制Wnt/β-连环蛋白可防止磷诱导的klotho下调。在HP培养基中添加CTR能够恢复klotho表达。总之，高FGF23水平增加FGFR1，而尿磷排泄通过激活Wnt/β-连环蛋白途径降低klotho表达。-穆尼奥斯-卡斯塔涅达，J.R.，埃雷西亚，C.，彭东-鲁伊斯·德米尔，M.V.，罗德里格斯-奥尔蒂斯，M.E.，迪亚兹-托卡多斯，J.M.，韦尔加拉，N.，马丁内斯-莫雷诺，J.M.，萨尔梅龙，M.D.，理查兹，W.G.，费尔森菲尔德，A.，黑濑，M.，阿尔马登，Y.，罗德里格斯，M.正常和尿毒症大鼠肾脏klotho和FGFR1的差异调节
