Publication

Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies

Mencke, R., Olauson, H. & Hillebrands, J-L., 1-Nov-2017, In : Advanced Drug Delivery Reviews. 121, p. 85-100 16 p.

Research output: Contribution to journalReview articleAcademicpeer-review

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 TGF beta 1 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 TGF beta 1, 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.

Original languageEnglish
Pages (from-to)85-100
Number of pages16
JournalAdvanced Drug Delivery Reviews
Volume121
Publication statusPublished - 1-Nov-2017

    Keywords

  • Klotho, Fibrosis, TGF beta 1, Wnt, FGF2, TRPC6, IGF1, ANTIAGING GENE KLOTHO, CHRONIC KIDNEY-DISEASE, CHRONIC CYCLOSPORINE NEPHROPATHY, UNILATERAL URETERAL OBSTRUCTION, HUMAN HEPATOCELLULAR-CARCINOMA, TRANSCRIPTS ENCODING MEMBRANE, AORTIC-VALVE CALCIFICATION, CIRCULATING ALPHA-KLOTHO, KINASE SIGNALING PATHWAY, RENIN-ANGIOTENSIN SYSTEM

View graph of relations

Download statistics

No data available

ID: 44193514