Histone demethylase UTX is a therapeutic target for diabetic kidney disease
Histone demethylase UTX is a therapeutic target for diabetic kidney disease
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组蛋白去甲基化酶 UTX 是糖尿病肾病的治疗靶点
DOI：
10.1113/jp277367
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发表时间：
2019-03-15
影响因子：
5.5
通讯作者：
Huang, Kun
中科院分区：
文献类型：
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作者：
Chen, Hong;Huang, Yixue;Huang, Kun
糖尿病肾病（DKD）是糖尿病的一种微血管并发症，是全球终末期肾病的主要原因，目前尚无有效的治疗方法。UTX（ubiquitously transcribed tetratricopeptide repeat on chromosome X，又称KDM 6A）是一种组蛋白去甲基化酶，能去除组蛋白H3 K27上的二甲基和三甲基，在秀丽隐杆线虫基因激活、细胞命运控制和寿命调节中发挥重要的生物学作用。在本研究中，我们报告上调UTX在糖尿病小鼠和DKD患者的肾脏。GSK-J 4（一种H3 K27去甲基化酶抑制剂）的施用改善了db/db小鼠（包括2型糖尿病的动物模型）中糖尿病诱导的肾功能障碍、异常形态、炎症、细胞凋亡和DNA损伤。在培养的肾系膜细胞和肾小管细胞中，UTX过表达促进棕榈酸诱导的炎症和DNA损伤的升高，而UTX敲低或GSK-J 4处理显示出相反的效果。从机制上讲，我们发现UTX去甲基化酶活性依赖性地调节炎症基因的转录;此外，UTX与p53结合，p53依赖性地加重DNA损伤。总的来说，我们的研究结果表明UTX作为DKD的潜在治疗靶点。
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.