Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice.
Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice.
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DOI：
10.1002/jbmr.401
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发表时间：
2011-08
影响因子：
6.2
通讯作者：
Perwad, Farzana
中科院分区：
文献类型：
--
作者：
Ranch, Daniel;Zhang, Martin Y. H.;Portale, Anthony A.;Perwad, Farzana
在 X 连锁低磷血症 (XLH) 及其小鼠同系物 Hyp 小鼠中，成纤维细胞生长因子 23 (FGF-23) 的循环浓度增加对于磷酸盐 (Pi) 和 1,25-二羟基维生素 D [1,25(OH)2D] 代谢紊乱的发病机制至关重要。在这项研究中，我们假设在 Hyp 小鼠中，FGF-23 介导的对肾脏 1,25(OH)2D 产生和 Pi 重吸收的抑制取决于丝裂原激活蛋白激酶 (MAPK) 信号的激活。野生型和 Hyp 小鼠每天口服载体或 MEK 抑制剂 PD0325901 (12.5 mg/kg)，持续 4 天。在基线时，Hyp 小鼠中早期生长反应 1 (egr1) mRNA 的肾脏丰度大约是野生型小鼠的 2 倍。 PD0325901 治疗极大地抑制了野生型和 Hyp 小鼠中的 egr1 mRNA 丰度。在 Hyp 小鼠中，与媒介物处理的 Hyp 小鼠相比，PD0325901 诱导肾脏 1α-羟化酶 mRNA 表达增加 8 倍，血清 1,25(OH)2D 浓度增加 4 倍。使用 PD0325901 治疗后，Hyp 小鼠的血清 Pi 水平显着增加，并且这种增加与肾脏 Npt2a mRNA 丰度和刷状缘膜 Npt2a 蛋白表达的增加有关。这些发现提供了证据，证明在 Hyp 小鼠中，MAPK 信号在肾脏中被组成性激活，并支持以下假设：FGF-23 介导的肾脏 1,25(OH)2D 产生和 Pi 重吸收的抑制取决于通过 MEK/ERK1/2 激活 MAPK 信号。这些发现证明了 MAPK 信号传导在 FGF-23 调节肾脏 1,25(OH)2D 和 Pi 代谢的作用中的生理重要性。
In X-linked hypophosphatemia (XLH) and in its murine homologue, the Hyp mouse, increased circulating concentrations of fibroblast growth factor 23 (FGF-23) are critical to the pathogenesis of disordered metabolism of phosphate (Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. In this study, we hypothesized that in Hyp mice, FGF-23-mediated suppression of renal 1,25(OH)2D production and Pi reabsorption depends on activation of mitogen-activated protein kinase (MAPK) signaling. Wild-type and Hyp mice were administered either vehicle or the MEK inhibitor PD0325901 (12.5 mg/kg) orally daily for 4 days. At baseline, the renal abundance of early growth response 1 (egr1) mRNA was approximately 2-fold greater in Hyp mice than in wild-type mice. Treatment with PD0325901 greatly suppressed egr1 mRNA abundance in both wild-type and Hyp mice. In Hyp mice, PD0325901 induced an 8-fold increase in renal 1α-hydroxylase mRNA expression and a 4-fold increase in serum 1,25(OH)2D concentrations compared with vehicle-treated Hyp mice. Serum Pi levels in Hyp mice increased significantly after treatment with PD0325901, and the increase was associated with increased renal Npt2a mRNA abundance and brush-border membrane Npt2a protein expression. These findings provide evidence that in Hyp mice, MAPK signaling is constitutively activated in the kidney and support the hypothesis that the FGF-23-mediated suppression of renal 1,25(OH)2D production and Pi reabsorption depends on activation of MAPK signaling via MEK/ERK1/2. These findings demonstrate the physiologic importance of MAPK signaling in the actions of FGF-23 in regulating renal 1,25(OH)2D and Pi metabolism.
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