Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Emergency Medicine and Difficult Diseases Institute, Central South University, Changsha, Hunan, People's Republic of China.
Theranostics. 2019 Apr 13;9(9):2712-2726. doi: 10.7150/thno.31424. eCollection 2019.
The molecular mechanism underlying the transition of acute kidney injury (AKI) to chronic kidney disease (CKD) induced by vancomycin (VAN) remains largely unknown. : 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. ChIp analysis was used to investigate if STAT3 interaction with the promoter of HIPK2. A novel VAN-induced AKI mouse model was established for the first time. Moreover, the expression levels collagen I&IV, α-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. ChIp 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. : These data suggest that EGFR plays an important role in VAN-driven progression of AKI to CKD.
万古霉素（VAN）诱导的急性肾损伤（AKI）向慢性肾脏病（CKD）转变的潜在分子机制在很大程度上尚不清楚。本研究旨在建立万古霉素诱导 AKI 向 CKD 转变的小鼠模型，探讨表皮生长因子受体（EGFR）的作用和分子机制。使用表皮生长因子受体突变（Wa-2）小鼠和吉非替尼来抑制 EGFR 的活性。应用同源结构域相互作用蛋白激酶 2（HIPK2）siRNA 沉默 HIPK2。使用人近端肾小管上皮细胞（HK-2）来探索 EGFR 的分子调控机制。应用 ChIP 分析来研究 STAT3 是否与 HIPK2 启动子相互作用。首次建立了一种新的万古霉素诱导的 AKI 小鼠模型。此外，在该模型中，I&IV 型胶原、α-SMA、磷酸化 EGFR 和 HIPK2 蛋白的表达水平上调。有趣的是，在早期，Wa-2 小鼠中，VAN 诱导的 AKI 明显减弱，表现为肾功能障碍、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明显改善，伴随着促纤维化分子和 F4/80 的下调。此外，在 VAN 诱导 AKI 向 CKD 转变过程中，Wa-2 小鼠的 HIPK2 和 p-STAT3 表达水平降低。此外，在 VAN 诱导 AKI 后，吉非替尼治疗可改善肾纤维化和炎症、促纤维化分子、EGFR/STAT3/HIPK2 信号通路。这些结果与 Wa-2 小鼠的发现一致。EGFR/STAT3 信号通路介导 VAN 诱导的 HK-2 细胞中 HIPK2 的表达。ChIP 分析显示，STAT3 直接与 HIPK2 启动子区域结合。最后，抑制 HIPK2 可减轻 VAN 驱动 AKI 向 CKD 进展。这些数据表明，EGFR 在 VAN 诱导的 AKI 向 CKD 进展中起重要作用。
