Histone demethylase UTX is a therapeutic target for diabetic kidney disease.
Hong ChenYixue HuangXiuqin ZhuChong LiuYangmian YuanHua SuChun ZhangChengyu LiuMingrui XiongYannan QuPeng YunLing ZhengKun HuangPublished in: The Journal of physiology (2018)
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.
Keyphrases
- oxidative stress
- dna damage
- induced apoptosis
- type diabetes
- diabetic rats
- dna repair
- dna methylation
- transcription factor
- cardiovascular disease
- cell cycle arrest
- signaling pathway
- end stage renal disease
- genome wide
- newly diagnosed
- high glucose
- chronic kidney disease
- ejection fraction
- endoplasmic reticulum stress
- copy number
- endothelial cells
- cell death
- stem cells
- escherichia coli
- bone marrow
- wound healing
- drug induced
- gene expression
- pseudomonas aeruginosa
- mesenchymal stem cells
- replacement therapy
- adipose tissue