Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA.
Department of Physiology and Pharmacology, College of Osteopathic Medicine, Sam Huston State University, Conroe, TX, USA.
Adv Exp Med Biol. 2022;1362:151-160. doi: 10.1007/978-3-030-91623-7_13.
The endocrine regulator proteins, fibroblast growth factor 23 (FGF23) and Klotho have been well studied as mediators of phosphate metabolism. FGF23 has been implicated in the renal excretion of phosphate by limiting the docking of sodium-dependent phosphate transporters, Npt2a and Npt2c, into the luminal side of renal proximal tubular epithelial cells. By limiting Npt2a/c activity in the renal tubular epithelial cells, phosphate is reabsorbed at lower rates and is excreted at higher rates. The action of Klotho is relatively less understood but has been implicated as an FGF23 cofactor in receptor binding. Klotho is mostly synthesized in the distal tubules of the nephron relative to FGF23's activity in proximal renal tubules. The neurological sequelae due to alterations in the FGF23-Klotho axis may be explained by the direct effects of these phosphate-regulating proteins on neuronal tissues or by the roles of these proteins in phosphate metabolism. Hyperphosphatemia has been associated with vascular wall stiffness that may alter blood flow and weakenvessels in the brain. In contrast, hypophosphatemia may alter ATP usage and metabolism in the central nervous system (CNS), leading to neurological compromise. Altered levels of FGF23 and Klotho have both been associated with neurocognitive decline, clinical dementia, memory loss, and poor executive function in humans. Furthermore, FGF23 and Klotho dysregulation has been linked to structural and functional changes of the cardiovascular system with an increased risk of stroke. Subsequent research should focus on characterizing the neuropathology associated with alterations in the FGF23-Klotho system and dysregulated phosphate metabolism.
内分泌调节蛋白，成纤维细胞生长因子 23（FGF23）和 Klotho，已被广泛研究为磷代谢的介质。FGF23 通过限制钠依赖性磷酸盐转运体 Npt2a 和 Npt2c 进入肾近端肾小管上皮细胞腔侧的结合，从而参与磷酸盐的肾脏排泄。通过限制肾肾小管上皮细胞中的 Npt2a/c 活性，磷酸盐以较低的速率被重吸收，以较高的速率被排泄。Klotho 的作用相对不太清楚，但已被暗示为受体结合的 FGF23 辅助因子。Klotho 主要在肾单位的远曲小管中合成，而 FGF23 的活性在肾近端小管中。由于 FGF23-Klotho 轴的改变而导致的神经后遗症可能是由这些磷酸盐调节蛋白对神经元组织的直接作用或这些蛋白在磷酸盐代谢中的作用所解释的。高磷血症与血管壁僵硬有关，可能改变血流并削弱大脑中的血管。相反，低磷血症可能改变中枢神经系统（CNS）中的 ATP 使用和代谢，导致神经功能障碍。FGF23 和 Klotho 水平的改变都与人类的神经认知能力下降、临床痴呆、记忆丧失和执行功能差有关。此外，FGF23 和 Klotho 的失调与心血管系统的结构和功能变化有关，增加了中风的风险。随后的研究应集中于描述与 FGF23-Klotho 系统改变和磷酸盐代谢失调相关的神经病理学。
