糖尿病条件下足细胞中谷氨酸受体亚型3的表达受表观遗传调控。
Expression of Glutamate Receptor Subtype 3 Is Epigenetically Regulated in Podocytes under Diabetic Conditions.
作者信息
Li Zhengzhe, Chen Haibing, Zhong Fang, Zhang Weijia, Lee Kyung, He John Cijiang
机构信息
Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
出版信息
Kidney Dis (Basel). 2019 Feb;5(1):34-42. doi: 10.1159/000492933. Epub 2018 Oct 26.
BACKGROUND
Recent studies suggest a role of epigenetics in the pathogenesis of diabetic kidney disease. However, epigenetic changes occurring specifically in kidney cells is poorly understood.
METHODS
To examine the epigenetic regulation of genes in podocytes under diabetic conditions, we performed DNA methylation and transcriptomic profiling in podocytes exposed to high glucose conditions.
RESULTS
Comparative analysis of genes with DNA methylation changes and correspondingly altered mRNA expression identified 337 hypomethylated genes with increased mRNA expression and only 2 hypermethyated genes ( and ) with decreased mRNA expression. Glutamate ionotropic receptor AMPA type subunit 3 () belongs to the ionotropic class of glutamate receptors that mediate fast excitatory synaptic transmission in the central nervous system. As podocytes have glutamate-containing vesicles and various glutamate receptors mediate important biological effects in podocytes, we further examined expression and its function in podocytes. Real-time PCR and western blots confirmed the suppression of expression in podocytes under high glucose conditions, which were abolished in the presence of a DNA methyltransferase inhibitor. Sites of DNA hypermethylation were also confirmed by bisulfite sequencing of the promoter region. mRNA and protein expression was suppressed in diabetic kidneys of human and mouse models, and knockdown of exacerbated high glucose-induced apoptosis in cultured podocytes.
CONCLUSION
These results indicate that decreased expression in podocytes in diabetic condition heightens podocyte apoptosis and loss.
背景
近期研究表明表观遗传学在糖尿病肾病发病机制中起作用。然而，肾脏细胞中特异性发生的表观遗传变化仍知之甚少。
方法
为了研究糖尿病条件下足细胞中基因的表观遗传调控，我们对暴露于高糖条件下的足细胞进行了DNA甲基化和转录组分析。
结果
对DNA甲基化变化和相应改变的mRNA表达的基因进行比较分析，鉴定出337个低甲基化基因，其mRNA表达增加，只有2个高甲基化基因（和），其mRNA表达降低。离子型谷氨酸受体AMPA 3型亚基（）属于离子型谷氨酸受体类别，介导中枢神经系统中的快速兴奋性突触传递。由于足细胞含有含谷氨酸的囊泡，并且各种谷氨酸受体在足细胞中介导重要的生物学效应，我们进一步研究了在足细胞中的表达及其功能。实时PCR和蛋白质印迹证实高糖条件下足细胞中表达受到抑制，而在存在DNA甲基转移酶抑制剂的情况下这种抑制作用被消除。启动子区域的亚硫酸氢盐测序也证实了DNA高甲基化位点。在人和小鼠模型的糖尿病肾脏中mRNA和蛋白质表达受到抑制，并且敲低加剧了培养的足细胞中高糖诱导的细胞凋亡。
结论
这些结果表明，糖尿病条件下足细胞中表达降低会加剧足细胞凋亡和丢失。
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