Knockout of Zeb2 ameliorates progression of renal tubulointerstitial fibrosis in a mouse model of renal ischemia?reperfusion injury
Knockout of Zeb2 ameliorates progression of renal tubulointerstitial fibrosis in a mouse model of renal ischemia?reperfusion injury
复制标题
Zeb2 敲除可改善肾缺血再灌注损伤小鼠模型中肾小管间质纤维化的进展
DOI：
10.1093/ndt/gfab311
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发表时间：
2021
影响因子：
6.1
通讯作者：
Terada Yoshio
中科院分区：
文献类型：
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作者：
Inotani Satoshi;Taniguchi Yoshinori;Nakamura Keisyun;Nishikawa Hirofumi;Matsumoto Tatsuki;Horino Taro;Fujimoto Shimpei;Sano Shigetoshi;Yanagita Motoko;Terada Yoshio
背景Zeb2 是一种锌指 E 盒结合同源盒转录因子，调节转化生长因子 (TGF)-β 信号通路。然而，其在急性肾损伤（AKI）和AKI向慢性肾病（CKD）转变的发病机制中的作用尚不清楚。方法我们使用近端小管特异性Zeb2条件敲除（Zeb2-cKO）和 结果：在 Zeb2-cKO 小鼠中，IRI 后血浆肌酐和血尿素氮水平显着低于 WT 小鼠。免疫组织学分析显示 IRI 后 3-14 天出现轻度肾小管损伤、中性粒细胞浸润减少、纤维化变化减少以及纤维化蛋白 [IV 型胶原、α-平滑肌肌动蛋白 (α-SMA)、纤连蛋白和结缔组织生长因子 (CTGF)] 表达减少。 WT 小鼠 IRI 后近端肾小管细胞中 Zeb2 表达上调。Zeb2siRNA 转染降低了培养的肾小管细胞中 TGF-β 刺激的 IV 型胶原、α-SMA、纤连蛋白和 CTGF 的 mRNA 和蛋白表达。肾活检显示，AKI 向 CKD 转变的患者在肾小管中表现出高 Zeb2 表达。缺氧和 CoCl2 处理上调了培养的肾小管上皮细胞中的 Zeb2 启动子活性以及 mRNA 和蛋白表达，表明缺氧具有调节作用。结论在 AKI 小鼠和人类的肾组织中，Zeb2 表达上调。 Zeb2 在 AKI 和 AKI 向 CKD 转变的发病机制中调节纤维化途径。因此，抑制 Zeb2 可能是 AKI 的潜在治疗策略。
BackgroundZeb2, a zinc finger E-box-binding homeobox transcription factor, regulates transforming growth factor (TGF)-βsignaling pathway. However, its role in the pathogenesis of acute kidney injury (AKI) and AKI-to-chronic kidney disease (CKD) transition is unclear.MethodsWe evaluated Zeb2 function in a bilateral renal ischemia–reperfusion injury (IRI)-induced AKI model using proximal tubule-specificZeb2conditional knockout (Zeb2-cKO) and wild-type (WT) mice, and in renal biopsy samples.ResultsIn Zeb2-cKO mice, the levels of plasma creatinine and blood urea nitrogen post-IRI were significantly lower than that in WT mice. Immunohistological analysis revealed mild tubular injury, reduced neutrophil infiltration, fewer fibrotic changes and reduced expression of fibrotic proteins [collagen type IV,α-smooth muscle actin (α-SMA), fibronectin and connective tissue growth factor (CTGF)], at 3–14 days post-IRI. Zeb2 expression was upregulated in proximal tubular cells post-IRI in WT mice.Zeb2siRNA transfection reduced TGF-β-stimulated mRNA and protein expression of collagen type IV,α-SMA, fibronectin and CTGF in cultured renal tubular cells. Patients with AKI-to-CKD transition exhibited high Zeb2 expression in renal tubules, as revealed by renal biopsy. Hypoxia and CoCl2-treatment upregulated Zeb2 promoter activity and mRNA and protein expression in cultured renal tubular epithelial cells, suggesting a regulatory role for hypoxia.ConclusionsZeb2 was upregulated in renal tissues in both mice and humans with AKI. Zeb2 regulates fibrotic pathways in the pathogenesis of AKI and AKI-to-CKD transition. Therefore, inhibition of Zeb2 could be a potential therapeutic strategy for AKI.