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α-Klotho Promotes Cell Death and Suppresses Inflammation through TNF-Cellular Inhibitor of Apoptosis Protein 1 Signaling in Autosomal Dominant Polycystic Kidney Disease
Journal article   Open access   Peer reviewed

α-Klotho Promotes Cell Death and Suppresses Inflammation through TNF-Cellular Inhibitor of Apoptosis Protein 1 Signaling in Autosomal Dominant Polycystic Kidney Disease

Linda Xiaoyan Li, Julie X. Zhou, Hongbing Zhang, James P. Calvet, Chou-Long Huang and Xiaogang Li
Journal of the American Society of Nephrology, Vol.37(5), pp.928-943
05/2026
DOI: 10.1681/ASN.0000000940
PMID: 41563399
url
https://doi.org/10.1681/ASN.0000000940View
Published (Version of record) Open Access

Abstract

Background α-Klotho (αKlotho) 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 αKlotho was lower in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the role of αKlotho in ADPKD remains unknown. Methods To investigate the roles of αKlotho in ADPKD, we generated transgenic αKlotho 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 αKlotho was lower in diverse kidney cell types in Pkd1 mutant kidneys, which was restored by transgenic αKlotho. We identified differential expression genes and pathways mediated by transgenic αKlotho 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 αKlotho 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 αKlotho also delayed cyst growth in Pkd1 mutant kidneys. Conclusions This study defined an unknown role and mechanism of αKlotho in the regulation of a TNF-dependent cystic cell apoptosis and inflammation in Pkd1 mutant kidneys.
 ADPKD cell death

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