Journal article
α-Klotho Promotes Cell Death and Suppresses Inflammation through TNF-Cellular Inhibitor of Apoptosis Protein 1 Signaling in Autosomal Dominant Polycystic Kidney Disease
Journal of the American Society of Nephrology, PMID 9013836
12/03/2025
DOI: 10.1681/ASN.0000000940
PMID: 41563399
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.
Details
- Title: Subtitle
- α-Klotho Promotes Cell Death and Suppresses Inflammation through TNF-Cellular Inhibitor of Apoptosis Protein 1 Signaling in Autosomal Dominant Polycystic Kidney Disease
- Creators
- Linda Xiaoyan Li - Mayo ClinicJulie X. Zhou - Mayo ClinicHongbing Zhang - University of Kansas Medical CenterJames P. Calvet - University of Kansas Medical CenterChou-Long Huang - University of IowaXiaogang Li - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Journal of the American Society of Nephrology, PMID 9013836
- DOI
- 10.1681/ASN.0000000940
- PMID
- 41563399
- NLM abbreviation
- J Am Soc Nephrol
- ISSN
- 1046-6673
- eISSN
- 1533-3450
- Publisher
- Wolters Kluwer
- Grant note
- National Institute of Diabetes and Digestive and Kidney Diseases: DK129241 Mayo Clinic: FP00121925 Department of Defense Education Activity: PR221810
X. Li: National Institute of Diabetes and Digestive and Kidney Diseases (DK129241, DK126662) and Department of Defense Education Activity (PR221810). L.X. Li: Mayo Clinic (FP00121925) and National Institute of Diabetes and Digestive and Kidney Diseases (U24DK126110). J.X.Zhou: National Institute of Diabetes and Digestive and Kidney Diseases (DK107729). J.P. Calvet: National Institute of Diabetes and Digestive and Kidney Diseases (DK126126). C.L. Huang (National Institute of Diabetes and Digestive and Kidney Diseases (DK111542 and DK100605).
- Language
- English
- Electronic publication date
- 12/03/2025
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9985121595302771
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