Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Abstract

Key points Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Abstract Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di‐ and tri‐methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

KDM6A mutations promote acute cytoplasmic DNA release, DNA damage response and mitosis defects

“…Thus, overexpressed (with a high dose-effect) and impaired KDM6A variants as well as oxygen-related stress have the tendency to increase DNA damage. This phenomenon was also observed in diabetic kidney disease (25). An additionally prominent feature of truncated KDM6A variants was a high degree of co-localization with NPM1 at extranuclear DNA and to appear, like all variants, as a mixed population of variable stoichiometry in the nucleoplasm (Fig.…”

Dysregulation of histone H3 lysine 27 trimethylation in transforming growth factor-β1–induced gene expression in mesangial cells and diabetic kidney

“…miR-101b targeting Ezh2, or genetic deletion of Ezh2 enhanced glomerular dysfunction (26,29), whereas Utx inhibitors ameliorated these effects in mice with renal injury and DN (29,39). Our current studies demonstrate that Ezh2 is down-regulated in RMCs, in human and mouse MCs treated with TGF-␤, and in glomeruli from diabetic rats, suggesting a conserved protective function in renal cells, although more studies are needed in different cell types.…”

Effects of metabolic memory on inflammation and fibrosis associated with diabetic kidney disease: an epigenetic perspective

“…Transient or previous hyperglycemia leads to various methylation and demethylation events that allow the pro-inflammatory pathways to be continuously activated, which further confirms the role of “metabolic memory” in DKD [ 40 ]. Moreover, the administration of the H3K27 demethylase inhibitor GSK-J4 improves renal dysfunction and reduces inflammation, apoptosis, and DNA damage in diabetic db/db mice [ 74 ].…”