Altered DNA methylation of TRIM13 in diabetic nephropathy suppresses mesangial collagen synthesis by promoting ubiquitination of CHOP
Altered DNA methylation of TRIM13 in diabetic nephropathy suppresses mesangial collagen synthesis by promoting ubiquitination of CHOP
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DOI：
10.1016/j.ebiom.2019.11.043
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发表时间：
2020-01-01
期刊：
影响因子：
11.1
通讯作者：
Xu, Gaosi
中科院分区：
文献类型：
--
作者：
Li, Yebei;Ren, Daijin;Xu, Gaosi
背景资料：糖尿病肾病（diabetic nephropathy，DN）是糖尿病最严重的并发症之一，系膜胶原的合成参与了DN的发病过程。然而，系膜胶原合成的基本机制在很大程度上是unknow.Methods：CHOP和TRIM 13，这是一个定义明确的E3泛素连接酶的差异表达进行了比较，在肾活检样品从DN/正常肾组织，在分离的肾小球糖尿病/对照小鼠，以及在高糖（HG）或TGF-β 1刺激的肾系膜细胞。结果：在糖尿病小鼠肾活检组织、离体肾小球和HG/TGF-β 1刺激的肾小球系膜细胞中，TRIM 13的表达下调，而CHOP的表达上调。TRIM 13基因启动子甲基化水平的升高促进了DN肾小球TRIM 13基因的失调。泛素化实验证实TRIM 13促进CHOP的泛素化和降解。同时，过表达TRIM 13减弱DN诱导的胶原合成，并通过下调CHOP.Interpretation在体外和体内恢复肾功能：我们的研究结果表明，过表达TRIM 13通过促进CHOP的泛素化抑制DN系膜胶原合成，提示TRIM 13作为治疗DN的潜在治疗靶点。(C)2019作者由爱思唯尔公司出版
Background: Mesangial collagen synthesis in renal glomeruli contributes to the pathogenesis of diabetic nephropathy (DN) which is one of the most serious complications of diabetes mellitus. However, the underlying mechanism of mesangial collagen synthesis is largely unknown.Methods: The differential expression of CHOP and TRIM13 which is a well-defined E3 ubiquitin ligase was compared in renal biopsy samples from DN/normal renal tissues, in isolated glomeruli of diabetic/control mice, as well as in high glucose (HG) or TGF-beta 1-stimulated renal mesangial cells. Then the relationship between TRIM13 and CHOP was explored using the ubiquitination assay.Findings: We found that the expression of TRIM13 was downregulated in renal biopsies, isolated glomeruli of diabetic mice, and HG/TGF-beta 1-stimulated renal mesangial cells, while the expression of CHOP was upregulated. An increased level of TRIM13 promoter methylation contributed to the deregulation of TRIM13 in renal glomeruli of DN. The ubiquitination assay confirmed that TRIM13 promoted ubiquitination and degradation of CHOP. Meanwhile, overexpressing TRIM13 attenuated DN-induced collagen synthesis and restored renal function in vitro and in vivo via downregulating CHOP.Interpretation: Our findings demonstrated that overexpressed TRIM13 suppresses mesangial collagen synthesis in DN by promoting ubiquitination of CHOP, suggesting TRIM13 as a potential therapeutic target in treating DN. (C) 2019 The Authors. Published by Elsevier B.V.