Inhibition of RNA-binding protein HuR reduces glomerulosclerosis in experimental nephritis.
Inhibition of RNA-binding protein HuR reduces glomerulosclerosis in experimental nephritis.
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DOI：
10.1042/cs20200193
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发表时间：
2020-06-26
期刊：
影响因子：
--
通讯作者：
Huang Y
中科院分区：
文献类型：
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作者：
Liu S;Huang Z;Tang A;Wu X;Aube J;Xu L;Xing C;Huang Y
最近鉴定出一种 RNA 结合蛋白 (HuR)，它通过与参与炎症的 3'-UTR 中的 ARE 结合来调节 mRNA 周转和大量转录物的翻译，并且在各种肾脏疾病中异常升高，为治疗肾脏炎症和随后的纤维化提供了新的靶点。因此，我们假设用小分子 KH-3 选择性抑制 HuR 功能的治疗将下调 HuR 靶向的促炎转录物，从而改善实验性肾炎中的肾小球硬化，其中肾小球细胞 HuR 升高。三个实验组包括用或不用 KH-3 治疗的正常和患病大鼠。疾病是由单克隆抗 Thy 1.1 抗体诱发的。从疾病诱导后第1天到第5天，每日腹腔注射KH-3，剂量为50 mg/kg BW/天。在第 6 天，与未经治疗的患病大鼠相比，用 KH-3 治疗的患病动物显示肾小球 HuR 水平、蛋白尿、足细胞损伤（通过改善足细胞损失和足细胞蛋白表达、肾小球高碘酸希夫阳性细胞外基质蛋白染色、纤连蛋白和 IV 型胶原以及促纤维化标志物的 mRNA 和蛋白水平）显着降低。 KH-3 治疗还减少了疾病引起的肾 TGFβ1 和 PAI-1 转录物的增加。此外，在疾病对照组中观察到的肾脏 NF-κB-p65、Nox4 和肾小球巨噬细胞浸润显着增加，在 KH-3 治疗后很大程度上得到逆转。这些结果有力地支持了我们的假设，即用 KH-3 下调 HuR 功能具有通过减少促炎转录物和相关炎症的丰度来逆转肾小球硬化的治疗潜力。
Recent identification of an RNA-binding protein (HuR) that regulates mRNA turnover and translation of numerous transcripts via binding to an ARE in their 3′-UTR involved in inflammation and is abnormally elevated in varied kidney diseases offers a novel target for the treatment of renal inflammation and subsequent fibrosis. Thus, we hypothesized that treatment with a selective inhibition of HuR function with a small molecule, KH-3, would down-regulate HuR-targeted proinflammatory transcripts thereby improving glomerulosclerosis in experimental nephritis, where glomerular cellular HuR is elevated. Three experimental groups included normal and diseased rats treated with or without KH-3. Disease was induced by the monoclonal anti-Thy 1.1 antibody. KH-3 was given via daily intraperitoneal injection from day 1 after disease induction to day 5 at the dose of 50 mg/kg BW/day. At day 6, diseased animals treated with KH-3 showed significant reduction in glomerular HuR levels, proteinuria, podocyte injury determined by ameliorated podocyte loss and podocin expression, glomerular staining for periodic acid-Schiff positive extracellular matrix proteins, fibronectin and collagen IV and mRNA and protein levels of profibrotic markers, compared with untreated disease rats. KH-3 treatment also reduced disease-induced increases in renal TGFβ1 and PAI-1 transcripts. Additionally, a marked increase in renal NF-κB-p65, Nox4, and glomerular macrophage cell infiltration observed in disease control group was largely reversed by KH-3 treatment. These results strongly support our hypothesis that down-regulation of HuR function with KH-3 has therapeutic potential for reversing glomerulosclerosis by reducing abundance of pro-inflammatory transcripts and related inflammation.