LncRNA ARAP1-AS2 promotes high glucose-induced human proximal tubular cell injury via persistent transactivation of the EGFR by interacting with ARAP1.
LncRNA ARAP1-AS2 promotes high glucose-induced human proximal tubular cell injury via persistent transactivation of the EGFR by interacting with ARAP1.
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DOI：
10.1111/jcmm.15897
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发表时间：
2020-11
影响因子：
5.3
通讯作者：
Fan QL
中科院分区：
文献类型：
--
作者：
Li X;Ma TK;Wen S;Li LL;Xu L;Zhu XW;Zhang CX;Liu N;Wang X;Fan QL
表皮生长因子受体（EGFR）的持续反式激活导致随后的TGF-β/Smad 3通路的激活，其与糖尿病肾病（DN）的纤维化和细胞增殖密切相关，但DN中持续EGFR反式激活的确切机制尚不清楚。ARAP 1是2型糖尿病的易感基因，可调节膜受体的内吞和泛素化，但ARAP 1及其天然反义长链非编码RNA（lncRNA）ARAP 1-AS 2对DN中EGFR泛素化的影响尚不清楚。在这项研究中，我们证实了ARAP 1和ARAP 1 ‐ AS 2的表达在高糖诱导的人近端肾小管上皮细胞（HK‐2细胞）中显著上调。此外，我们发现过表达或敲低ARAP 1-AS 2可以通过EGFR/TGF-β/Smad 3信号传导调节纤维化和HK-2细胞增殖。RNA pulldown分析显示ARAP 1 ‐ AS 2直接与ARAP 1相互作用。免疫共沉淀、双重免疫荧光和泛素化分析表明，ARAP 1可能通过与Cbl竞争CIN 85结合，减少EGFR泛素化，从而维持EGFR的持续活化。综上所述，我们的结果表明lncRNA ARAP 1-AS 2可能通过与ARAP 1相互作用，通过持续的EGFR/TGF-β/Smad 3通路激活，促进高糖诱导的近端肾小管细胞损伤。
The persistent transactivation of epidermal growth factor receptor (EGFR) causes subsequent activation of the TGF‐β/Smad3 pathway, which is closely associated with fibrosis and cell proliferation in diabetic nephropathy (DN), but the exact mechanism of persistent EGFR transactivation in DN remains unclear. ARAP1, a susceptibility gene for type 2 diabetes, can regulate the endocytosis and ubiquitination of membrane receptors, but the effect of ARAP1 and its natural antisense long non‐coding RNA (lncRNA), ARAP1‐AS2, on the ubiquitination of EGFR in DN is not clear. In this study, we verified that the expression of ARAP1 and ARAP1‐AS2 was significantly up‐regulated in high glucose‐induced human proximal tubular epithelial cells (HK‐2 cells). Moreover, we found that overexpression or knockdown of ARAP1‐AS2 could regulate fibrosis and HK‐2 cell proliferation through EGFR/TGF‐β/Smad3 signalling. RNA pulldown assays revealed that ARAP1‐AS2 directly interacts with ARAP1. Coimmunoprecipitation, dual‐immunofluorescence and ubiquitination assays showed that ARAP1 may maintain persistent EGFR activation by reducing EGFR ubiquitination through competing with Cbl for CIN85 binding. Taken together, our results suggest that the lncRNA ARAP1‐AS2 may promote high glucose‐induced proximal tubular cell injury via persistent EGFR/TGF‐β/Smad3 pathway activation by interacting with ARAP1.
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DOI：
10.2147/dddt.s143805
发表时间：
2017
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Tang F;Hao Y;Zhang X;Qin J
通讯作者：
Qin J
lncRNA—ARAP1—AS2/ARAP1对高糖诱导的人肾小管上皮细胞细胞骨架重排和上皮—间质转化的影响
影响因子：
5.6
作者：
Li, Lulu;Xu, Li;Fan, Qiuling
通讯作者：
Fan, Qiuling
影响因子：
9.8
作者：
Kulzer, Jennifer R.;Stitzel, Michael L.;Mohlke, Karen L.
通讯作者：
Mohlke, Karen L.
影响因子：
64.8
作者：
Soubeyran, P;Kowanetz, K;Dikic, I
通讯作者：
Dikic, I
ceRNA网络中的拓扑关键lncRNA H2k2通过miR-449a/b/Trim11/Mek信号通路促进糖尿病肾病肾小球系膜细胞增殖
影响因子：
4.8
作者：
Chen, Wenyun;Peng, Rui;Zhang, Zheng
通讯作者：
Zhang, Zheng