Cypermethrin (CYP), a widely-used composite pyrethroid pesticide, has underlying nephrotoxic effects. To elucidate potential roles of the MAPK pathway, the Jag/Notch pathway, and miRNAs in CYP-mediated kidney lesion, Sprague-Dawley rats and glomerular mesangial cells were used in this work. Results displayed that β-CYP abnormally altered renal histomorphology and ultrastructures, induced renal DNA damage, and impaired renal functions, as evidenced by the increase in plasma levels of Cys-C and β2-Mg. β-CYP activated the JNK/c-Jun pathway by inducing ROS and oxidative stress. Meanwhile, β-CYP changed the miRNA expression profile, miR-21–5p showing the most significant increase. Moreover, the Jag1/Notch2/Hes1 pathway was directly targeted by miR-21–5p, the mRNA and protein expression of Jag1, Notch2, and Hes1 being declined in vivo and in vitro. The chemokine CXCL16 was induced by β-CYP, accompanied by the inflammatory factor production and inflammatory cell infiltration in kidneys. The specific JNK inhibitor, Jag1 overexpression, Hes1 overexpression, bidirectional Co-IP, ChIP, and CXCL16 silencing demonstrated that CXCL16 co-regulated by the JNK/c-Jun and Jag1/Notch2/Hes1 pathways elicited renal inflammation. Collectively, our findings indicate that β-CYP is of nephrotoxicity and it not only directly changes renal histomorphology and ultrastructures, but induces CXCL16 to trigger renal inflammation via the JNK/c-Jun and Jag1/Notch2/Hes1 pathways, finally synergistically contributing to kidney damage.

氯氰菊酯 (CYP) 是一种广泛使用的复合拟除虫菊酯杀虫剂，具有潜在的肾毒性作用。为了阐明 MAPK 通路、Jag/Notch 通路和 miRNA 在 CYP 介导的肾脏病变中的潜在作用，在这项工作中使用了 Sprague-Dawley 大鼠和肾小球系膜细胞。结果表明，β-CYP 异常改变肾脏组织形态学和超微结构，诱导肾脏 DNA 损伤，并损害肾功能，这可以通过血浆 Cys-C 和 β2-Mg 水平的增加来证明。β-CYP 通过诱导 ROS 和氧化应激激活 JNK/c-Jun 通路。同时，β-CYP 改变了 miRNA 的表达谱，miR-21-5p 的增加最为显着。此外，Jag1/Notch2/Hes1 通路被 miR-21-5p 直接靶向，Jag1、Notch2 和 Hes1 的 mRNA 和蛋白表达在体内和体外均下降。趋化因子 CXCL16 由 β-CYP 诱导，伴随着肾脏炎症因子的产生和炎症细胞浸润。特异性 JNK 抑制剂、Jag1 过表达、Hes1 过表达、双向 Co-IP、ChIP 和 CXCL16 沉默表明，由 JNK/c-Jun 和 Jag1/Notch2/Hes1 通路共同调节的 CXCL16 可引发肾脏炎症。总的来说，我们的研究结果表明 β-CYP 具有肾毒性，它不仅直接改变肾脏的组织形态和超微结构，而且通过 JNK/c-Jun 和 Jag1/Notch2/Hes1 途径诱导 CXCL16 引发肾脏炎症，最终协同促进肾脏损害。Hes1 过表达、双向 Co-IP、ChIP 和 CXCL16 沉默表明，由 JNK/c-Jun 和 Jag1/Notch2/Hes1 通路共同调节的 CXCL16 会引发肾脏炎症。总的来说，我们的研究结果表明 β-CYP 具有肾毒性，它不仅直接改变肾脏的组织形态和超微结构，而且通过 JNK/c-Jun 和 Jag1/Notch2/Hes1 途径诱导 CXCL16 引发肾脏炎症，最终协同促进肾脏损害。Hes1 过表达、双向 Co-IP、ChIP 和 CXCL16 沉默表明，由 JNK/c-Jun 和 Jag1/Notch2/Hes1 通路共同调节的 CXCL16 会引发肾脏炎症。总的来说，我们的研究结果表明 β-CYP 具有肾毒性，它不仅直接改变肾脏的组织形态和超微结构，而且通过 JNK/c-Jun 和 Jag1/Notch2/Hes1 途径诱导 CXCL16 引发肾脏炎症，最终协同促进肾脏损害。