Epigenetic Regulation of KL (Klotho) via H3K27me3 (Histone 3 Lysine [K] 27 Trimethylation) in Renal Tubule Cells

Hypertension. 2020 May;75(5):1233-1241. doi: 10.1161/HYPERTENSIONAHA.120.14642. Epub 2020 Mar 30.

Abstract

KL (klotho) levels decline with age, which is an important mechanistic driver of aging. KL gene deficiency is associated with hypertension. The purpose of this study is to investigate the potential role of H3K27me3 (histone 3 lysine [K] 27 trimethylation) in the regulation of KL gene expression and examine the related molecular pathways that may drive kidney cell aging. Kidneys were collected from 6-month-old WT (wild type; young WT), 30-month-old WT (aged WT), and 6- (young) and 20-month-old (aged) KL mutant mice, respectively. We demonstrated that the H3K27me3 level was increased in kidneys of aged WT and KL mutant mice versus young WT mice. Elevation of H3K27me3 levels was likely due to downregulation of the H3K27 (histone H3 Lys 27)-specific demethylase JMJD3 (the Jumonji domain containing-3) in the aged kidneys. Inhibition of PRC2 (polycomb repressive complex C2; histone trimethyltransferase) decreased the H3K27me3 levels leading to an increase in the expression of KL in cultured primary renal tubule cells assessed by Western blot and KL promoter activity assays. The chromatin immunoprecipitation qPCR assay revealed that H3K27me3 was physically associated with the KL promoter region. Furthermore, aging impaired the SGK1 (serum- and glucocorticoid-induced protein kinase 1)/FOXO3a (the forkhead box class O 3a) signaling leading to upregulation of p53 and p16 (aging markers) in the kidney of aged WT mice. KL may regulate the SGK1/FOXO3 signaling, which was decreased due to KL deficiency. Thus, aging-associated downregulation of KL gene expression may be partly attributed to upregulation of H3K27me3 levels. Downregulation of KL may impair the SGK1/FOXO3 signaling contributing to kidney cell aging.

Keywords: AKT; EZH2; aging; mTOR; p53.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / genetics*
  • Aging / metabolism
  • Animals
  • Blotting, Western
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Enhancer of Zeste Homolog 2 Protein / biosynthesis
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enzyme Induction
  • Forkhead Box Protein O3 / metabolism
  • Gene Expression Regulation / genetics*
  • Glucuronidase / biosynthesis
  • Glucuronidase / deficiency
  • Glucuronidase / genetics*
  • Histone Code*
  • Histones / genetics*
  • Histones / metabolism
  • Immediate-Early Proteins / metabolism
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Kidney / growth & development
  • Kidney Tubules / cytology
  • Kidney Tubules / metabolism*
  • Klotho Proteins
  • Male
  • Methylation
  • Mice
  • Promoter Regions, Genetic
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Forkhead Box Protein O3
  • FoxO3 protein, mouse
  • Histones
  • Immediate-Early Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm6b protein, mouse
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • mTOR protein, mouse
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Glucuronidase
  • Klotho Proteins