Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Yakushiji, Shimotsuke, Tochigi, Japan.
Nephrol Dial Transplant. 2019 Jan 1;34(1):15-21. doi: 10.1093/ndt/gfy126.
Three members of the fibroblast growth factor (FGF) family, FGF19, FGF21 and FGF23, are different from the other members in two major aspects. First, they are actually not growth factors but endocrine factors that regulate various metabolic processes. Second, their physiological receptors are not FGF receptors (FGFRs) but binary complexes of FGFRs and Klotho proteins. FGF23 and FGF21 have emerged as biomarkers that start increasing in early-stage chronic kidney disease (CKD). FGF23 is a bone-derived phosphaturic hormone that binds to the αKlotho-FGFR complex expressed in renal tubules to increase phosphate excretion per nephron. The FGF23 increase is deemed necessary to compensate for the decrease in the nephron number during CKD progression and to maintain the phosphate balance. However, the increase in phosphate excretion per nephron induces renal tubular damage and accelerates nephron loss. CKD progression is also associated with an increase in calciprotein particles (CPPs) in the blood. CPPs are calcium-phosphate nanoparticles with the ability to induce endothelial damage and inflammatory responses. The fact that serum CPP levels are correlated with vascular calcification/stiffness and mortality in CKD patients suggests that CPPs may serve as a 'pathogen' of cardiovascular complications. Like FGF23, FGF21 starts increasing in early-stage CKD. FGF21 is a liver-derived hormone that binds to the βKlotho-FGFR complex expressed in the central nervous system to induce stress responses, including activation of the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis. Thus FGF21 and FGF23 are not merely biomarkers for CKD progression but potential pathogenic agents that accelerate CKD progression and aggravate cardiovascular complications.
成纤维细胞生长因子 (FGF) 家族的三个成员，FGF19、FGF21 和 FGF23，在两个主要方面与其他成员不同。首先，它们实际上不是生长因子，而是调节各种代谢过程的内分泌因子。其次，它们的生理受体不是 FGF 受体 (FGFR)，而是 FGFR 和 Klotho 蛋白的二元复合物。FGF23 和 FGF21 已成为早期慢性肾脏病 (CKD) 开始升高的生物标志物。FGF23 是一种骨源排磷激素，与在肾小管中表达的 αKlotho-FGFR 复合物结合，增加每个肾单位的磷酸盐排泄。FGF23 的增加被认为是必需的，以补偿 CKD 进展过程中肾单位数量的减少，并维持磷酸盐平衡。然而，每个肾单位磷酸盐排泄的增加会导致肾小管损伤并加速肾单位丢失。CKD 进展还与血液中钙磷蛋白颗粒 (CPPs) 的增加有关。CPPs 是具有诱导内皮损伤和炎症反应能力的钙磷纳米颗粒。血清 CPP 水平与 CKD 患者的血管钙化/僵硬和死亡率相关的事实表明，CPPs 可能是心血管并发症的“病原体”。与 FGF23 一样，FGF21 在早期 CKD 中开始增加。FGF21 是一种肝脏来源的激素，与在中枢神经系统中表达的βKlotho-FGFR 复合物结合，诱导应激反应，包括激活交感神经系统和下丘脑-垂体-肾上腺轴。因此，FGF21 和 FGF23 不仅是 CKD 进展的生物标志物，还是加速 CKD 进展和加重心血管并发症的潜在致病因子。
