Department of Laboratory Medicine and Pathobiology, University of Toronto, 220 Walmer Rd, Toronto, ON M5R 3R7, Canada.
Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, ON M5B 1W8, Canada.
Cells. 2024 Aug 24;13(17):1413. doi: 10.3390/cells13171413.
The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer's disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications.
α-klotho 蛋白（以下简称 klotho）是成纤维细胞生长因子 23（FGF23）的必需核心受体。它在肾脏、大脑和其他部位产生。klotho 不足会导致高磷血症和其他异常。重要的是，它与具有炎症成分的慢性病理有关（通常与年龄有关）。这包括动脉粥样硬化、糖尿病和阿尔茨海默病。其在这些疾病中的作用机制尚不清楚，但它抑制或调节多种主要途径。klotho 有膜型和可溶性型（s-Klotho）。细胞溶质 klotho 被假设存在，但特征描述不足。s-Klotho 具有不完全阐明的内分泌特性。它与广泛表达（包括内皮细胞）的成纤维细胞生长因子受体 1c（FGFR1c）结合。它还附着在可溶性 FGF23 上，而 FGF23/klotho 与 FGFRs 结合。因此，s-Klotho 可能是一个漫游的 FGF23 核心受体，但它还有其他功能。值得注意的是，klotho（细胞结合或可溶性）对抗炎症，似乎减轻相关衰老（炎症衰老）。它抑制 NF-κB 和 NLRP3 炎性体。这种炎性体需要 NF-κB 的启动，并产生活性 IL-1β、膜孔和细胞死亡（pyroptosis）。klotho 抵消了毒素、损伤相关分子模式（DAMPs）、细胞因子和活性氧（ROS）引起的炎症和细胞损伤。s-Klotho 还阻断 TGF-β 受体和 Wnt 配体，从而减少纤维化疾病。klotho 减少与肌肉质量减少（肌肉减少症）有关，如衰老和慢性疾病中发生的那样。s-Klotho 抵消了肌肉生长抑制素和 TGF-β 对肌肉的抑制作用，减少了炎症，并改善了损伤后的肌肉修复。TGF-β 和其他因素的抑制也可能对糖尿病性视网膜病变和年龄相关性黄斑变性（AMD）具有保护作用。这篇综述检查了 klotho 的功能，特别是与炎症的关系以及潜在的应用。
