Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies.
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.
['Mencke|Rik|R|', 'Olauson|Hannes|H|', 'Hillebrands|Jan-Luuk|JL|']
D000818:Animals D000970:Antineoplastic Agents D049109:Cell Proliferation D005355:Fibrosis D005966:Glucuronidase D006801:Humans D007674:Kidney Diseases D000090265:Klotho Proteins D009369:Neoplasms
Klotho Fibrosis TGFβ1 Wnt FGF2 IGF1 TRPC6