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Kidney Week

Abstract: TH-PO799

Epigenetic Downregulation of Klotho via H3K27me3 Associated with Suppression of SGK-1 Survival Signaling in Aged Mouse Kidney

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Han, Xiaobin, University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Sun, Zhongjie, University of Tennessee Health Sciences Center, Memphis, Tennessee, United States

Klotho deficiency is an important mechanistic driver of cell aging. However, the underlying mechanisms by which how Klotho is downregulated by epigenetics in aging cell have not been clearly elucidated.


In this study, we examined the role of H3K27me3 in the regulation of Klotho gene expression and pathways that influence the cell aging in the kidney of 30-months-old wild type (aged WT) C57BL/6 mice, and Klotho mutant mice compared to 6-months-old WT (young) mice, respectively.


We demonstrated that the level of H3K27me3 was increased in the kidney of aged WT and Klotho mutant mice compared to young WT mice. Elevation of H3K27me3 was largely due to the downregulation of the histone 3 lysine 27 specific demethylase UTX and/or JMJD3 in the aging kidneys. Inhibition of Polycomb Repressive Complex C 2 (PRC2) using EED226 and GSK343 decreased the expression of H3K27me3 leading to increase in the expression of Klotho in primary cultured renal tubule cells determined by Western blot and Klotho promoter assay. Inhibition of PRC2 reduced level of H3K27me3 associated with Klotho promoter, suggesting that epigenetic downregulation of Klotho gene expression was due, at least in part, to histone 3 modification in the Klotho promoter region. ChIP qPCR revealed that H3K27me3 was enriched in the Klotho promoter region in the kidney of aged WT and Klotho mutant mice compared to young WT mice. Furthermore, our results showed that aging impaired SGK-1/FOXO3a signaling leading to upregulation of p53 and p16 in the kidney of aged WT and Klotho mutant mice.


We have first shown that epigenetic modification of histone mark H3K27me3 directly downregulates Klotho in the kidney of aged wild type mice. Aging exerts renal effects through hyperphosphorylation of mTOR which is independent of Klotho status. The normal aging and Klotho-deficient mediated aging share a common pathway through impaired SGK1 survival signaling leading to upregulation of FOXO3a, p53 and p16 in the kidney of aged WT and Klotho mutant mice. Thus, hormonal action of Klotho may be an alternative approach to activating SGK1 survival signaling for treating aging-mediated kidney disorders.


  • Other NIH Support