Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis.
Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis.
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DOI：
10.1186/s12967-023-04298-x
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发表时间：
2023-06-30
影响因子：
7.4
通讯作者：
Huang, Yufeng
中科院分区：
文献类型：
--
作者：
Huang, Zhimin;Liu, Simeng;Tang, Anna;Wu, Xiaoqing;Aube, Jeffrey;Xu, Liang;Huang, Yufeng
RNA 结合蛋白 HuR 的上调与肾小球疾病有关。在此，我们评估其是否参与肾小管纤维化。 HuR 首先在患有肾小管疾病的人肾活检组织中进行检测。其次，在单侧肾缺血/再灌注（IR）诱导的小鼠模型中进一步评估了其表达以及用 KH3 抑制 HuR 对肾小管损伤的影响。 IR 后第 3 天至第 14 天，每天通过腹腔注射给予 KH3（50 mg kg−1）。最后，在培养的近端肾小管细胞中检查了 HuR 靶向途径之一。在进行性 CKD 患者和小鼠 IR 损伤肾脏中，肾小管损伤部位的 HuR 显着增加，并伴有与炎症、促纤维化细胞因子、氧化应激、增殖、细胞凋亡、肾小管 EMT 过程、基质重塑和肾小管间质纤维化中的纤维化相关的 HuR 靶点上调。 KH3 治疗可减少 IR 引起的肾小管损伤和纤维化，同时显着改善相关通路。一组 mRNA 阵列进一步显示，IR 损伤后小鼠肾脏中的 519 个分子的表达发生了变化，其中 71.3% 的参与 50 条促纤维化途径的分子在用 KH3 治疗后得到了改善。在体外，TGFβ1 诱导肾小管 HuR 细胞质易位和随后的肾小管 EMT，在培养的 HK-2 细胞中施用 KH3 可消除这种现象。这些结果表明，HuR 的过度上调通过调节参与多种促纤维化途径的基因并激活肾小管细胞中的 TGFβ1/HuR 反馈回路，从而导致肾小管间质纤维化。抑制 HuR 可能具有治疗肾小管纤维化的潜力。在线版本包含可在 10.1186/s12967-023-04298-x 获取的补充材料。
Upregulation of an RNA-binding protein HuR has been implicated in glomerular diseases. Herein, we evaluated whether it is involved in renal tubular fibrosis. HuR was firstly examined in human kidney biopsy tissue with tubular disease. Second, its expression and the effect of HuR inhibition with KH3 on tubular injury were further assessed in a mouse model induced by a unilateral renal ischemia/reperfusion (IR). KH3 (50 mg kg−1) was given daily via intraperitoneal injection from day 3 to 14 after IR. Last, one of HuR-targeted pathways was examined in cultured proximal tubular cells. HuR significantly increases at the site of tubular injury both in progressive CKD in patients and in IR-injured kidneys in mice, accompanied by upregulation of HuR targets that are involved in inflammation, profibrotic cytokines, oxidative stress, proliferation, apoptosis, tubular EMT process, matrix remodeling and fibrosis in renal tubulointerstitial fibrosis. KH3 treatment reduces the IR-induced tubular injury and fibrosis, accompanied by the remarkable amelioration in those involved pathways. A panel of mRNA array further revealed that 519 molecules in mouse kidney following IR injury changed their expression and 71.3% of them that are involved in 50 profibrotic pathways, were ameliorated when treated with KH3. In vitro, TGFβ1 induced tubular HuR cytoplasmic translocation and subsequent tubular EMT, which were abrogated by KH3 administration in cultured HK-2 cells. These results suggest that excessive upregulation of HuR contributes to renal tubulointerstitial fibrosis by dysregulating genes involved in multiple profibrotic pathways and activating the TGFß1/HuR feedback circuit in tubular cells. Inhibition of HuR may have therapeutic potential for renal tubular fibrosis. The online version contains supplementary material available at 10.1186/s12967-023-04298-x.
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