EGFR drives the progression of AKI to CKD through HIPK2 overexpression
EGFR drives the progression of AKI to CKD through HIPK2 overexpression
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EGFR 通过 HIPK2 过表达驱动 AKI 进展为 CKD。
DOI：
10.7150/thno.31424
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhang, Dongshan
中科院分区：
文献类型：
--
作者：
Xu, Luyang;Li, Xiaozhou;Zhang, Dongshan
急性肾损伤（AKI）向慢性肾脏疾病（CKD）诱导的分子机制（van）仍在很大程度上未知。表皮生长因子受体（EGFR）。 EGF受体突变体（WA-2）小鼠和吉非替尼用于灭活EGFR。同源域相互作用的蛋白激酶2（HIPK2）siRNA用于HIPK2的静音。人类近端管状上皮细胞（HK-2）用于探索EGFR的分子调节甲烷。使用CHLP分析来研究STAT3是否与Hipk2的启动子进行相互作用：首次建立了新型的Van诱导的AKI小鼠模型。此外，在该模型中，表达水平胶原蛋白I和IV，α-SMA，P-EGFR和HIPK2蛋白的表达被上调。有趣的是，在早期，由货车引起的AKI在波浪-2小鼠中显着减弱，这证明了肾功能障碍，肾细胞凋亡和caspase3激活的抑制。在后期，WA-2小鼠的肾纤维化和炎症显着改善，并伴随着纤维纤维分子和F4/80的下调。此外，在VAN诱导AKI向CKD的过渡期间，WA-2小鼠的HIPK2和P-STAT3的表达水平被抑制。此外，肾纤维化和炎症，纤维化分子和EGFR/STAT3/HIPK2信号通过GEFITINIB处理在VAN诱导的AKI后通过吉非替尼进行改善。这些结果与WA-2小鼠的发现一致。 EGFR/STAT3信号传导介导的VAN诱导的HK-2细胞中的HIPK2表达。 CHLP分析表明，STAT3直接与HIPK2的启动子区域结合。最后，抑制HIPK2减弱了货车将AKI的进展驱动到CKD。结论：这些数据表明，EGFR在AKI向CKD的Van驱动进展中起重要作用。
The molecular mechanism underlying the transition of acute kidney injury (AKI) to chronic kidney disease (CKD) induced by vancomycin (VAN) remains largely unknown.Methods: The mice model of VAN drives AKI to CKD was developed to investigate the role and molecular mechanism of epidermal growth factor receptor (EGFR). The EGF receptor mutant (Wa-2) mice and gefitinib were used to inactivation of EGFR. The homeodomain interacting protein kinase 2 (HIPK2) siRNA was applied to silence of HIPK2. Human proximal tubular epithelial cells (HK-2) were used to explore the molecular regulation methanism of EGFR. Chlp analysis was used to investigate if STAT3 interaction with the promoter of HIPK2.Results: A novel VAN-induced AKI mouse model was established for the first time. Moreover, the expression levels collagen I&IV, alpha-SMA, p-EGFR and the expression of HIPK2 proteins were upregulated in this model. Interestingly, AKI caused by VAN was markedly attenuated in waved-2 mice at the early stage, as evidenced by the suppression of renal dysfunction, renal cell apoptosis and caspase3 activation. In the latter stage, renal fibrosis and inflammation were significantly ameliorated in Wa-2 mice, accompanied by the downregulation of profibrotic molecules and F4/80. Besides, the expression levels of HIPK2 and p-STAT3 were suppressed in Wa-2 mice during VAN-induced transition of AKI to CKD. In addition, renal fibrosis and inflammation, profibrotic molecules, and EGFR/STAT3/HIPK2 signaling were ameliorated by gefitinib treatment after VAN-induced AKI. These results were consistent with the findings of Wa-2 mice. EGFR/STAT3 signaling mediated VAN-induced HIPK2 expression in HK-2 cells. Chlp analysis revealed that STAT3 directly bound to the promoter region of HIPK2. Finally, inhibition of HIPK2 attenuated the VAN drove the progression of AKI to CKD.Conclusion: These data suggest that EGFR plays an important role in VAN-driven progression of AKI to CKD.