Klotho Attenuates ADPKD Progression by Epigenetic Reprogramming and Multimodal Suppression of Cystogenic Pathways

Le résumé fourni par la source

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent hereditary nephropathy caused by PKD1 or PKD2 mutations, often progressing to end-stage kidney disease (ESKD). Klotho, a renoprotective protein with anti-aging functions, has emerged as a potential modulator of disease progression, though its mechanistic role in ADPKD remains unclear. Methods: We investigated Klotho expression in Pkd1-deficient cell lines, ADPKD mouse models, and human kidney tissues. Functional assays assessed the effects of recombinant Klotho on proliferation, fibrosis, ferroptosis, and inflammation. DNA methylation profiling, chromatin immunoprecipitation (ChIP), and DNMT1 inhibition explored the epigenetic regulation of Klotho. Results: Klotho expression was significantly reduced in ADPKD, associated with DNMT1-mediated hypermethylation of the Klotho promoter. Exogenous Klotho treatment delayed disease progression. Mechanistically, Klotho inhibited key cystogenic signaling pathways, including PI3K-AKT, JAK2-STAT3, and NF-κB. It also attenuated ferroptosis via upregulation of GPX-4 and reduced TGF-β-mediated fibrosis. Conclusion: This study identifies Klotho as a critical suppressor of ADPKD progression through epigenetic and signaling modulation. Targeting the DNMT1-Klotho axis offers a promising therapeutic approach for halting cyst growth, inflammation, and fibrosis in ADPKD.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.