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-β1-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-β1-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.

中文翻译：

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糖尿病肾病中TRIM13 DNA甲基化的改变通过促进CHOP的泛素化来抑制肾小球膜胶原合成。

背景技术肾小球中的肾小球系膜胶原蛋白合成是糖尿病性肾病（DN）的发病机理，这是糖尿病最严重的并发症之一。但是，肾小球系膜胶原蛋白合成的基本机制尚不清楚。方法比较了DN /正常肾脏组织，糖尿病/对照小鼠分离的肾小球以及高血糖（HG）或TGF的肾活检样本中CHOP和TRIM13（一种明确定义的E3泛素连接酶）的差异表达。 -β1刺激的肾小球膜细胞。然后使用泛素化分析探索了TRIM13和CHOP之间的关系。结果发现，TRIM13的表达在肾活检，糖尿病小鼠的肾小球和HG /TGF-β1刺激的肾小球膜细胞中被下调，而CHOP的表达上调。TRIM13启动子甲基化水平的升高有助于DN肾小球中TRIM13的失调。泛素化测定证实TRIM13促进了CHOP的泛素化和降解。同时，过表达TRIM13可通过下调CHOP的作用而减弱DN诱导的胶原蛋白合成，并在体内和体外恢复肾功能。解释我们的发现表明，过表达的TRIM13通过促进CHOP的泛素化来抑制DN中的系膜胶原合成，这表明TRIM13是治疗DN的潜在治疗靶标。同时，过表达TRIM13可通过下调CHOP的作用而减弱DN诱导的胶原蛋白合成，并在体内和体外恢复肾功能。解释我们的发现表明，过表达的TRIM13通过促进CHOP的泛素化而抑制DN中的系膜胶原合成，这表明TRIM13是治疗DN的潜在治疗靶标。同时，过表达TRIM13可通过下调CHOP的作用而减弱DN诱导的胶原蛋白合成，并在体内外恢复肾功能。解释我们的发现表明，过表达的TRIM13通过促进CHOP的泛素化而抑制DN中的系膜胶原合成，这表明TRIM13是治疗DN的潜在治疗靶标。