Conditional Deletion of Fgfr1 in the Proximal and Distal Tubule Identifies Distinct Roles in Phosphate and Calcium Transport.
Conditional Deletion of Fgfr1 in the Proximal and Distal Tubule Identifies Distinct Roles in Phosphate and Calcium Transport.
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DOI：
10.1371/journal.pone.0147845
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Quarles LD
中科院分区：
文献类型：
--
作者：
Han X;Yang J;Li L;Huang J;King G;Quarles LD
成纤维细胞生长因子受体-1 （FGFR1）与α-Klotho结合，形成激素成纤维细胞生长因子-23 （FGF-23）的专性受体，表明其在出生后在肾脏中的作用。FGFR1在肾小管近端和远端均有表达，但其小管特异性功能尚不清楚。在这项研究中，我们将Fgfr1flox/flox小鼠与γ -谷氨酰转移酶- cre （γGT-Cre）或肾特异性cre （kp - cre）小鼠杂交，选择性地产生近端小管（PT）和远端小管（DT） Fgfr1条件敲除小鼠（分别命名为Fgfr1PT-cKO和Fgfr1DT-cKO）。Fgfr1PT-cKO小鼠表现出钠依赖性磷酸盐共转运蛋白表达增加、高磷血症和对FGF-23的磷酸化作用的难反应，这与FGFR1在介导近端小管磷酸盐对FGF-23的反应中的直接作用一致。相反，Fgfr1DT-cKO小鼠出人意料地出现高钙尿症、继发性甲状旁腺激素（PTH）升高、低磷血症和尿磷酸盐排泄增强。Fgfr1PT-cKO小鼠也出现卷曲尾巴/脊柱裂样骨骼表型，而Fgfr1DT-cKO小鼠出现肾小管微钙化和皮质骨厚度减少。因此，FGFR1具有直接调节近端和远端小管磷酸盐和钙重吸收的双重功能，表明FGFR1信号传导在磷酸盐和钙稳态中的生理作用。
A postnatal role of fibroblast growth factor receptor-1 (FGFR1) in the kidney is suggested by its binding to α-Klotho to form an obligate receptor for the hormone fibroblast growth factor-23 (FGF-23). FGFR1 is expressed in both the proximal and distal renal tubular segments, but its tubular specific functions are unclear. In this study, we crossed Fgfr1flox/flox mice with either gamma-glutamyltransferase-Cre (γGT-Cre) or kidney specific-Cre (Ksp-Cre) mice to selectively create proximal tubule (PT) and distal tubule (DT) Fgfr1 conditional knockout mice (designated Fgfr1PT-cKO and Fgfr1DT-cKO, respectively). Fgfr1PT-cKO mice exhibited an increase in sodium-dependent phosphate co-transporter expression, hyperphosphatemia, and refractoriness to the phosphaturic actions of FGF-23, consistent with a direct role of FGFR1 in mediating the proximal tubular phosphate responses to FGF-23. In contrast, Fgfr1DT-cKO mice unexpectedly developed hypercalciuria, secondary elevations of parathyroid hormone (PTH), hypophosphatemia and enhanced urinary phosphate excretion. Fgfr1PT-cKO mice also developed a curly tail/spina bifida-like skeletal phenotype, whereas Fgfr1DT-cKO mice developed renal tubular micro-calcifications and reductions in cortical bone thickness. Thus, FGFR1 has dual functions to directly regulate proximal and distal tubule phosphate and calcium reabsorption, indicating a physiological role of FGFR1 signaling in both phosphate and calcium homeostasis.