C 型利钠肽通过抑制 FGF-23/MAPK 信号传导来减轻肾性骨营养不良。,Experimental & Molecular Medicine

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C 型利钠肽通过抑制 FGF-23/MAPK 信号传导来减轻肾性骨营养不良。
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2019-07-01 , DOI: 10.1038/s12276-019-0265-8
Dong Dong Zhang ₁ , Yang Fang Wu ₁ , Wei Xia Chen ₁ , Yao Xu ₁ , Si Yan Liu ₁ , Huang Huang Luo ₁ , Guang Mei Jiang ₁ , Yue Wu ₁ , Peng Hu ₁

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肾性骨营养不良 (ROD) 早在慢性肾脏病 (CKD) 2 期时就发生了，并且似乎在几乎所有 CKD 5 期的儿科患者中普遍存在。成纤维细胞生长因子 (FGF)-23 是一种磷酸盐稳态的骨源性内分泌调节剂，是在 CKD 中过表达并干扰成骨细胞分化和基质矿化。相比之下，C 型利钠肽 (CNP) 可作为骨骼生长的有效正调节剂。在本研究中，我们将 CNP 注入尿毒症大鼠，观察 CNP 是否可以通过抑制 FGF-23 级联来减弱 ROD。在尿毒症大鼠中，CNP 给药显着减轻肾功能障碍、磷酸钙代谢紊乱、维生素 D 缺乏、继发性甲状旁腺功能亢进、骨转换标志物减少和延缓骨病理进展。更重要的是，在 FGF-23/丝裂原活化蛋白激酶 (MAPK) 信号传导中，成纤维细胞生长因子受体 1、Klotho 和替代 (STAT-1/磷酸-STAT-1) 元件被 CNP 上调，而 FGF-23、RAF- 1/磷酸-RAF-1 和下游（ERK/磷酸-ERK 和 P38/磷酸-P38）元件在骨组织中反常地低表达。因此，CNP 通过在 RAF-1 水平抑制 FGF-23/MAPK 信号传导对 ROD 发挥治疗作用。

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C-type natriuretic peptide attenuates renal osteodystrophy through inhibition of FGF-23/MAPK signaling.

Renal osteodystrophy (ROD) occurs as early as chronic kidney disease (CKD) stage 2 and seems ubiquitous in almost all pediatric patients with CKD stage 5. Fibroblast growth factor (FGF)-23, a bone-derived endocrine regulator of phosphate homeostasis, is overexpressed in CKD and disturbs osteoblast differentiation and matrix mineralization. In contrast, C-type natriuretic peptide (CNP) acts as a potent positive regulator of bone growth. In the present study, we infused CNP into uremic rats and observed whether CNP could attenuate ROD through the inhibition of FGF-23 cascades. In uremic rats, CNP administration significantly alleviated renal dysfunction, calcium phosphate metabolic disorders, hypovitaminosis D, secondary hyperparathyroidism, the decrease in bone turnover markers and retarded bone pathological progression. More importantly, within FGF-23/mitogen-activated protein kinase (MAPK) signaling, the fibroblast growth factor receptor-1, Klotho and alternative (STAT-1/phospho-STAT-1) elements were upregulated by CNP, whereas FGF-23, RAF-1/phospho-RAF-1, and downstream (ERK/phospho-ERK and P38/phospho-P38) elements were paradoxically underexpressed in bone tissue. Therefore, CNP exerts a therapeutic effect on ROD through inhibition of FGF-23/MAPK signaling at the RAF-1 level.

更新日期：2019-07-01

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