Klotho is a membrane-bound protein predominantly expressed in the kidney, where it acts as a permissive co-receptor for Fibroblast Growth Factor 23. In its shed form, Klotho exerts anti-fibrotic effects in several tissues. Klotho-deficient mice spontaneously develop fibrosis and Klotho deficiency exacerbates the disease progression in fibrotic animal models. Furthermore, Klotho overexpression or supplementation protects against fibrosis in various models of renal and cardiac fibrotic disease. These effects are mediated at least partially by the direct inhibitory effects of soluble Klotho on TGFβ1 signaling, Wnt signaling, and FGF2 signaling. Soluble Klotho, as present in the circulation, appears to be the primary mediator of anti-fibrotic effects. Similarly, through inhibition of the TGFβ1, Wnt, FGF2, and IGF1 signaling pathways, Klotho also inhibits tumorigenesis. The Klotho promoter gene is generally hypermethylated in cancer, and overexpression or supplementation of Klotho has been found to inhibit tumor growth in various animal models. This review focuses on the protective effects of soluble Klotho in inhibiting renal fibrosis and fibrosis in distant organs secondary to renal Klotho deficiency. We also discuss the structure-function relationships of Klotho domains and biological effects in the context of potential targeted treatment strategies.

Klotho是一种主要在肾脏中表达的膜结合蛋白，在其中充当成纤维细胞生长因子23的允许共受体。Klotho以脱落的形式在多个组织中发挥抗纤维化作用。Klotho缺陷小鼠自发地发展为纤维化，Klotho缺陷在纤维化动物模型中加剧了疾病的进展。此外，在肾脏和心脏纤维化疾病的各种模型中，Klotho的过量表达或补充可防止纤维化。这些作用至少部分地由可溶性Klotho对TGFβ1信号传导，Wnt信号传导和FGF2信号传导的直接抑制作用介导。循环中存在的可溶性Klotho似乎是抗纤维化作用的主要介质。同样，通过抑制TGFβ1，Wnt，FGF2和IGF1信号通路，Klotho还抑制肿瘤发生。Klotho启动子基因通常在癌症中甲基化，并且在各种动物模型中发现Klotho的过表达或补充均会抑制肿瘤的生长。这篇综述的重点是可溶性Klotho在抑制肾纤维化以及继发于肾Klotho缺乏的远处器官的纤维化中的保护作用。我们还讨论了潜在的靶向治疗策略中Klotho域的结构与功能之间的关系以及生物学效应。这篇综述的重点是可溶性Klotho在抑制肾纤维化以及继发于肾Klotho缺乏的远处器官的纤维化中的保护作用。我们还讨论了潜在的靶向治疗策略中Klotho域的结构与功能之间的关系以及生物学效应。这篇综述的重点是可溶性Klotho在抑制肾纤维化以及继发于肾Klotho缺乏的远处器官的纤维化中的保护作用。我们还讨论了潜在的靶向治疗策略中Klotho域的结构与功能之间的关系以及生物学效应。