Division of Nephrology, Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Curr Opin Nephrol Hypertens. 2019 Jan;28(1):16-25. doi: 10.1097/MNH.0000000000000467.
The current review examines what is known about the FGF-23/α-Klotho co-dependent and independent pathophysiological effects, and whether FGF-23 and/or α-Klotho are potential therapeutic targets.
FGF-23 is a hormone derived mainly from bone, and α-Klotho is a transmembrane protein. Together they form a trimeric signaling complex with FGFRs in target tissues to mediate the physiological functions of FGF-23. Local and systemic factors control FGF-23 release from osteoblast/osteocytes in bone, and circulating FGF-23 activates FGFR/α-Klotho complexes in kidney proximal and distal renal tubules to regulate renal phosphate excretion, 1,25 (OH)2D metabolism, sodium and calcium reabsorption, and ACE2 and α-Klotho expression. The resulting bone-renal-cardiac-immune networks provide a new understanding of bone and mineral homeostasis, as well as identify other biological effects FGF-23. Direct FGF-23 activation of FGFRs in the absence of α-Klotho is proposed to mediate cardiotoxic and adverse innate immune effects of excess FGF-23, particularly in chronic kidney disease, but this FGF-23, α-Klotho-independent signaling is controversial. In addition, circulating soluble Klotho (sKl) released from the distal tubule by ectodomain shedding is proposed to have beneficial health effects independent of FGF-23.
Separation of FGF-23 and α-Klotho independent functions has been difficult in mammalian systems and understanding FGF-23/α-Klotho co-dependent and independent effects are incomplete. Antagonism of FGF-23 is important in treatment of hypophosphatemic disorders caused by excess FGF-23, but its role in chronic kidney disease is uncertain. Administration of recombinant sKl is an unproven therapeutic strategy that theoretically could improve the healt span and lifespan of patients with α-Klotho deficiency.
本综述探讨了 FGF-23/α-Klotho 依赖性和独立性病理生理作用的已知内容，以及 FGF-23 和/或 α-Klotho 是否为潜在的治疗靶点。
FGF-23 是一种主要来源于骨骼的激素，α-Klotho 是一种跨膜蛋白。它们共同形成三聚体信号复合物，与靶组织中的 FGFR 结合，介导 FGF-23 的生理功能。局部和全身因素控制骨骼中骨细胞/成骨细胞中 FGF-23 的释放，循环中的 FGF-23 激活肾脏近端和远端肾小管中的 FGFR/α-Klotho 复合物，调节肾脏磷酸盐排泄、1,25(OH)2D 代谢、钠和钙重吸收以及 ACE2 和 α-Klotho 的表达。由此产生的骨-肾-心-免疫网络提供了对骨骼和矿物质稳态的新认识，并确定了 FGF-23 的其他生物学作用。据推测，在没有 α-Klotho 的情况下，FGF-23 直接激活 FGFR 介导过量 FGF-23 的心脏毒性和先天免疫不良作用，尤其是在慢性肾脏病中，但这种 FGF-23、α-Klotho 非依赖性信号传递存在争议。此外，通过蛋白水解从远端小管释放的循环可溶性 Klotho（sKl）被提议具有独立于 FGF-23 的有益健康作用。
在哺乳动物系统中，将 FGF-23 和 α-Klotho 的独立功能分开一直很困难，对 FGF-23/α-Klotho 依赖性和独立性的作用认识尚不完整。拮抗 FGF-23 对治疗由过量 FGF-23 引起的低磷血症疾病很重要，但在慢性肾脏病中的作用尚不确定。重组 sKl 的给药是一种未经证实的治疗策略，理论上可以改善 α-Klotho 缺乏患者的健康寿命和预期寿命。
