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Kidney Week

Abstract: PO1235

Reduction of Klotho Promotes Cyst Growth and Epigenetic Age Acceleration in ADPKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Li, Xiaoyan, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Zhang, Xiaoqin, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Zhou, Xia, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Calvet, James P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Huang, Chou-Long, The University of Iowa Hospitals and Clinics Department of Pathology, Iowa City, Iowa, United States
  • Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
Background

Symptoms of ADPKD vary in severity and age of onset and tend to accelerate quickly in older patients, eventually resulting in kidney failure. αKlotho has been identified as an anti-aging protein, and the kidney is the organ expressing the highest levels of αKlotho protein and the main origin for systemic αKlotho. The soluble serum form of αKlotho (extracellular domain of αKlotho) was found to be decreased in ADPKD patients, however, the role of αKlotho in ADPKD remains unknown.

Methods

To investigate the role and mechanism of αKlotho in ADPKD, we introduced an αKlotho transgene into Pkd1 conditional knockout mice and performed single cell RNA sequencing (scRNA-seq) in kidneys collected at postnatal days 7, 14 and 21 to determine the differentially expressed genes (DEGs) and signaling pathways mediated by αKlotho in different renal cell types. The expression of key DEGs identified with scRNA-seq was confirmed with qRT-PCR analysis.

Results

We found that full length αKlotho was decreased in collecting duct cells, macrophages, fibroblasts and T/NK immune cells in Pkd1 homozygous kidneys. Transgenic αKlotho delayed cyst growth in Pkd1 conditional knockout mice by normalizing the expression of genes associated with a number of diverse functions, including the genes associated with the transitions between collecting duct cell subtypes and genes involved in epigenetic mechanisms. In addition, we found that the genes associated with the epigenetic clock (DNA methylation age) were dysregulated in those cells in cystic kidneys, and that they could be normalized by transgenic αKlotho, suggesting that transgenic αKlotho might slow down the process of epigenetic age acceleration in cystic kidneys. The dysregulation of the epigenetic age-acceleration genes, Apoe, Cldn4, Mgp and Slc38a2, might contribute to PKD pathogenesis and might serve as potential biomarkers for ADPKD. Finally, transgenic αKlotho affected a large number of genes associated with metabolic and oxidative signaling, suggesting that αKlotho might act by slowing down metabolic processes to extend the life span of mice.

Conclusion

Reduction of aKlotho regulates cyst growth through diverse signaling pathways. Pkd1 mutation accelerates epigenetic age in ADPKD. Transgenic aKlotho not only delayed cyst growth but also slowed down epigenetic age acceleration.

Funding

  • NIDDK Support