Department of Neurology, Medical University of Warsaw, Second Faculty of Medicine, Bielanski Hospital, Warsaw, Poland.
Neuro Endocrinol Lett. 2020 Sep;41(2):69-75.
Klotho is a transmembrane protein with a wide spectrum of activity. The human Klotho gene shows 86% amino acid identity with the mouse protein. Many important pleiotropic functions of the Klotho protein have been revealed. Amongst them, there is a regulation of nitric oxide production, suppression of oxidative stress and inflammation, influence on the insulin-like growth factors and fibroblast growth factors signaling, modulation of calcium and phosphate metabolism, synthesis of vitamin D and other. Two forms of the Klotho protein are known. The secreted form strongly inhibits the oxidative stress, and, in humans, is more dominant than the membrane form. Studies on a mouse model resulted in the finding of the anti-aging effect of the Klotho protein. This activity is mainly associated with the suppression of oxidative stress, as well as it could be related to neuroprotective, cardioprotective, and metabolic functions.It might be speculated that Klotho, regarded as a neuroprotective factor, may have therapeutical applications in the future in the treatment of demyelinating and neurodegenerative disorders, especially multiple sclerosis (MS) and Alzheimer's disease (AD). The Klotho through inhibition of oxidative stress possesses cardioprotective properties. Of note, one functional variant of Klotho is a risk factor for coronary disease as well as some nucleotide polymorphisms are associated with carotid arteriosclerosis. Moreover, the Klotho protein can inhibit Angiotensin II-induced cardiomyocyte hypertrophy. All those effects indicate that the Klotho protein may be useful in the therapy of heart failure and hypertension. Undoubtedly, metabolic disturbances play an important role in the pathogenesis of many neurodegenerative and cardiovascular diseases. The metabolic effects of the Klotho protein are strongly connected with its neuroprotective and cardioprotective activity. This protein affects adipogenesis, metabolism of glucose and lipids as well as calcium-phosphate system by influence on the activity of fibroblast growth factors (FGF19, FGF23, FGF21). Finally, it has been revealed that the Klotho protein has antitumor activity. Besides, the FGF-Klotho system may have a role in longevity and aging-related disorders.
Klotho 是一种具有广泛活性的跨膜蛋白。人类 Klotho 基因与小鼠蛋白的氨基酸序列具有 86%的同源性。Klotho 蛋白的许多重要的多效性功能已被揭示。其中包括调节一氧化氮的产生、抑制氧化应激和炎症、影响胰岛素样生长因子和成纤维细胞生长因子信号、调节钙磷代谢、合成维生素 D 等。已知有两种 Klotho 蛋白形式。分泌型强烈抑制氧化应激，在人类中比膜型更占优势。对小鼠模型的研究发现 Klotho 蛋白具有抗衰老作用。这种活性主要与抑制氧化应激有关，也可能与神经保护、心脏保护和代谢功能有关。可以推测，Klotho 作为一种神经保护因子，在未来可能在治疗脱髓鞘和神经退行性疾病，特别是多发性硬化症（MS）和阿尔茨海默病（AD）方面具有治疗应用。Klotho 通过抑制氧化应激具有心脏保护作用。值得注意的是，Klotho 的一种功能变体是冠心病的危险因素，一些核苷酸多态性与颈动脉粥样硬化有关。此外，Klotho 蛋白可以抑制血管紧张素 II 诱导的心肌细胞肥大。所有这些作用表明，Klotho 蛋白可能对心力衰竭和高血压的治疗有用。毫无疑问，代谢紊乱在许多神经退行性和心血管疾病的发病机制中起着重要作用。Klotho 蛋白的代谢作用与其神经保护和心脏保护活性密切相关。这种蛋白通过影响成纤维细胞生长因子（FGF19、FGF23、FGF21）的活性，影响脂肪生成、葡萄糖和脂质代谢以及钙磷系统。最后，已经揭示 Klotho 蛋白具有抗肿瘤活性。此外，FGF-Klotho 系统可能在长寿和与衰老相关的疾病中发挥作用。
