α-Klotho Promotes Cell Death and Suppresses Inflammation through TNF–Cellular Inhibitor of Apoptosis Protein 1 Signaling in Autosomal Dominant Polycystic Kidney Disease
Year: 2025
Type: article
Abstract: KEY POINTS: α Klotho as an antiaging protein can extend the lifespan of healthy animals; serum α Klotho was lower in patients with autosomal dominant polycystic kidney disease. Transgenic α Klotho and recombinant α Klotho delayed cyst growth in Pkd1 mutant mouse kidneys. α Klotho exerted its proapoptotic and anti-inflammatory function through interacting with and destabilizing cellular inhibitor of apoptosis protein 1. BACKGROUND: α -Klotho ( α Klotho) is expressed mainly in the kidney, which is encoded by the KL gene, existing in a membrane-bound form and a soluble circulating form. Soluble serum α Klotho was lower in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the role of α Klotho in ADPKD remains unknown. METHODS: To investigate the roles of α Klotho in ADPKD, we generated transgenic α Klotho and Pkd1 mutant Pkd1-HOMO-KLTg mice to evaluate cyst growth and investigated underlying mechanisms with single-cell RNA sequencing analysis. RESULTS: We showed that α Klotho was lower in diverse kidney cell types in Pkd1 mutant kidneys, which was restored by transgenic α Klotho. We identified differential expression genes and pathways mediated by transgenic α Klotho at single-cell resolution and determined the cytokines and their receptors mediated cell-to-cell communication networks in Pkd1 mutant and Pkd1-HOMO-KLTg kidneys by CellChat analysis. We further showed that α Klotho exerted a proapoptotic and anti-inflammatory function through interacting with and destabilizing cellular inhibitor of apoptosis protein 1, which disturbed TNF and its receptor mediated prosurvival complex, leading to ( 1 ) the formation of predeath complex to increase cystic cell death and ( 2 ) the decrease of the activation of NF-κB, the expression of cytokines, and the recruitment of macrophages, resulting in a delay of cyst growth. Treatment with recombinant α Klotho also delayed cyst growth in Pkd1 mutant kidneys. CONCLUSIONS: This study defined an unknown role and mechanism of α Klotho in the regulation of a TNF-dependent cystic cell apoptosis and inflammation in Pkd1 mutant kidneys.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Awards: G2760050405, G3302989134, The crosstalk of DNA and lysine methyltransferases in ADPKD., Crosstalk of DNMT1 and Sirt1 in Autosomal Dominant Polycystic Kidney Disease, Klotho and chronic kidney disease, G4006116896, G4465707179, G6231550562, G7120080638, G7891225457, ADPKD: Understanding immunosuppression mechanisms and discovering treatment, G8417201434, WNK kinase cascade in health and disease, Central Coordinating Site for the Polycystic Kidney Disease (PKD) Research Core Centers, Kansas PKD Research and Translation Core Center
OpenAlex ID: W7122617608