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MicroRNA-214 targets COX-2 to antagonize indoxyl sulfate (IS)-induced endothelial cell apoptosis

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Abstract

Cardiovascular disease (CVD) serves as the major cause of mortality in chronic kidney disease (CKD) patients. The injury of endothelium associated with the long-term challenge of uremic toxins including the toxic indoxyl sulfate (IS) is one of key pathological factors leading to CVD. However, the mechanisms of uremic toxins, especially the IS, resulting in endothelial injury, remain unclear. miR-214 was reported to contribute to the pathogenesis of cardiovascular diseases, while its role in IS-induced endothelial cell apoptosis is unknown. In this study, we investigated the role of microRNA-214 (miR-214) in IS-induced endothelial cell apoptosis and the underlying mechanisms using mouse aortic endothelial cells (MAECs). Following IS treatment, miR-214 was significantly downregulated in MAECs in line with enhanced cell apoptosis. Meanwhile, COX-2 was upregulated at both mRNA and protein levels along with increased secretion of PGE2 in medium. To define the role of miR-214 in IS-induced endothelial cell apoptosis, we modulated miR-214 level in MAECs and found that overexpression of miR-214 markedly attenuated endothelial cell apoptosis, while antagonism of miR-214 deteriorated cell death after IS challenge. Further analyses confirmed that COX-2 is a target gene of miR-214, and the inhibition of COX-2 by a specific COX-2 inhibitor NS-398 strikingly attenuated IS-induced endothelial cell apoptosis along with a significant blockade of PGE2 secretion. In conclusion, this study demonstrated an important role of miR-214 in protecting against endothelial cell damage induced by IS possibly by direct downregulation of COX-2/PGE2 axis.

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Funding

This work was supported by Grants from the National Natural Science Foundation of China (Nos. 81770740, 81400750, 81670647, 81600557, 81530023, 81570643, 81873599, and 81570616), the National Key Research and Development Program (No. 2016YFC0906103), the Natural Science Foundation of Jiangsu Province (No. BK20130077), and Nanjing City Key Medical Research Project (Nos. ZKX16057, ZKX16059, ZKX18039).

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Authors and Affiliations

  1. Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People’s Republic of China

    Shuzhen Li, Yifan Xie, Bingyu Yang, Songming Huang, Yue Zhang, Zhanjun Jia, Guixia Ding & Aihua Zhang

  2. Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China

    Shuzhen Li, Yifan Xie, Bingyu Yang, Songming Huang, Yue Zhang, Zhanjun Jia, Guixia Ding & Aihua Zhang

  3. Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, China

    Shuzhen Li, Yifan Xie, Bingyu Yang, Songming Huang, Yue Zhang, Zhanjun Jia, Guixia Ding & Aihua Zhang

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  1. Shuzhen Li
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Li, S., Xie, Y., Yang, B. et al. MicroRNA-214 targets COX-2 to antagonize indoxyl sulfate (IS)-induced endothelial cell apoptosis. Apoptosis 25, 92–104 (2020). https://doi.org/10.1007/s10495-019-01582-4

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