Identification of NOD2 as a novel target of RNA-binding protein HuR: evidence from NADPH oxidase-mediated HuR signaling in diabetic nephropathy
Identification of NOD2 as a novel target of RNA-binding protein HuR: evidence from NADPH oxidase-mediated HuR signaling in diabetic nephropathy
复制标题
鉴定 NOD2 作为 RNA 结合蛋白 HuR 的新靶标：糖尿病肾病中 NADPH 氧化酶介导的 HuR 信号转导的证据
DOI：
10.1016/j.freeradbiomed.2014.12.013
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发表时间：
2015-02-01
影响因子：
7.4
通讯作者：
Yi, Fan
中科院分区：
文献类型：
--
作者：
Shang, Jin;Wan, Qiang;Yi, Fan
尽管我们最近的研究表明NOD 2是糖尿病肾病（DN）中连接肾损伤和炎症的信号转导通路的关键组分之一，但高血糖下NOD 2表达的调节机制尚未阐明。考虑到不同物种的NOD 2 mRNA都有一个长的3 '-UTR，并含有各种富含AU的元件，本研究旨在研究RNA结合蛋白人抗原R（HuR）对NOD 2表达的转录后调控的潜在作用。在本研究中，我们首次发现糖尿病肾病患者的肾脏中HuR表达上调，这与蛋白尿相关，表明HuR在糖尿病肾病的发病机制中起作用。在体外，高糖（HG）诱导大鼠肾小球系膜细胞胞浆HuR明显增加。通过RNA EMSA，我们发现HuR与NOD 2的3 '-UTR结合，并且HuR沉默降低HG诱导的NOD 2表达和mRNA稳定性。从机制上讲，我们进一步发现NADPH氧化酶介导的氧化还原信号有助于HuR和NOD 2 mRNA稳定性的表达和易位。最后，我们评估了HuR的作用，表明通过肾内慢病毒基因递送的HuR的体内基因沉默改善了糖尿病大鼠的肾损伤以及降低了NOD 2的表达。总的来说，我们的研究表明，HuR作为NOD 2表达的关键转录后调节因子，这表明靶向HuR-NOD 2信号转导可能对DN的治疗至关重要。(C)2014爱思唯尔公司All rights reserved.
Although our recent studies have demonstrated that NOD2 is one of the critical components of a signal transduction pathway that links renal injury to inflammation in diabetic nephropathy (DN), the regulatory mechanisms for NOD2 expression under hyperglycemia have not yet been elucidated. Considering that NOD2 mRNA from different species bears a long 3'-UTR with various AU-rich elements, the present study was designed to investigate the potential contribution of the RNA-binding protein human antigen R (HuR) on the posttranscriptional regulation of NOD2 expression. In this study, we first found upregulation of HuR in the kidney from DN subjects, which was correlated with proteinuria, indicating a role for HuR in the pathogenesis of DN. In vitro, high glucose (HG) induced a distinct increase in cytoplasmic HuR in rat glomerular mesangial cells. By RNA EMSA, we found that HuR bound to the 3'-UTR of NOD2, and HuR silencing reduced HG-induced NOD2 expression and mRNA stability. Mechanistically, we further found that NADPH oxidase-mediated redox signaling contributed to the expression and translocation of HuR and NOD2 mRNA stability. Finally, we evaluated the role of HuR showing that in vivo gene silencing of HuR by intrarenal lentiviral gene delivery ameliorated renal injury as well as reducing NOD2 expression in diabetic rats. Collectively, our studies demonstrate that HuR acts as a key posttranscriptional regulator of NOD2 expression, suggesting that targeting of HuR-NOD2 signaling might be crucial for the treatment of DN. (C) 2014 Elsevier Inc. All rights reserved.