Platelet-derived extracellular vesicles aggravate septic acute kidney injury via delivering ARF6

Lu, Xun; Jiang, Guiya; Gao, Yue; Chen, Qi; Sun, Si; Mao, Weipu; Zhang, Nieke; Zhu, Zepeng; Wang, Dong; Zhang, Guangyuan; Chen, Ming; Zhang, Lei; Chen, Shuqiu

doi:10.7150/ijbs.87165

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Int J Biol Sci 2023; 19(16):5055-5073. doi:10.7150/ijbs.87165 This issue Cite

Research Paper

Platelet-derived extracellular vesicles aggravate septic acute kidney injury via delivering ARF6

Xun Lu^1,2*, Guiya Jiang^1,2*, Yue Gao^1,2*, Qi Chen^3*, Si Sun^1,2, Weipu Mao^1,2, Nieke Zhang^1,2, Zepeng Zhu^1,2, Dong Wang^1,2, Guangyuan Zhang^1,2, Ming Chen^1,2✉, Lei Zhang^1,2✉, Shuqiu Chen^1,2✉

1. Department of Urology, Affiliated Zhongda hospital of Southeast University, Nanjing, China.
2. Surgical Research Center, Institute of Urology, School of Medicine, Southeast University, Nanjing, China.
3. Department of Interventional Radiology and Vascular Surgery, Affiliated Zhongda hospital of Southeast University, Nanjing, China.
* These authors contributed equally to this work.

Citation:

Lu X, Jiang G, Gao Y, Chen Q, Sun S, Mao W, Zhang N, Zhu Z, Wang D, Zhang G, Chen M, Zhang L, Chen S. Platelet-derived extracellular vesicles aggravate septic acute kidney injury via delivering ARF6. Int J Biol Sci 2023; 19(16):5055-5073. doi:10.7150/ijbs.87165. https://www.ijbs.com/v19p5055.htm

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Abstract

Circulating plasma extracellular vesicles (EVs) mostly originate from platelets and may promote organ dysfunction in sepsis. However, the role of platelet-derived EVs in sepsis-induced acute kidney injury (AKI) remains poorly understood. The present study extracted EVs from the supernatant of human platelets treated with phosphate buffer saline (PBS) or lipopolysaccharide (LPS). Then, we subjected PBS-EVs or LPS-EVs to cecal ligation and puncture (CLP) mice in vivo or LPS-stimulated renal tubular epithelial cells (RTECs) in vitro. Our results indicated that LPS-EVs aggravate septic AKI via promoting apoptosis, inflammation and oxidative stress. Further, ADP-ribosylation factor 6 (ARF6) was identified as a differential protein between PBS-EVs and LPS-EVs by quantitative proteomics analysis. Mechanistically, ARF6 activated ERK/Smad3/p53 signaling to exacerbate sepsis-induced AKI. LPS upregulated ARF6 in RTECs was dependent on TLR4/MyD88 pathway. Both genetically and pharmacologically inhibition of ARF6 attenuated septic AKI. Moreover, platelets were activated by TLR4 and its downstream mediator IKK controlled platelet secretion during sepsis. Inhibition of platelet secretion alleviated septic AKI. Collectively, our study demonstrated that platelet-derived EVs may be a therapeutic target in septic AKI.

Keywords: sepsis, extracellular vesicles, platelet, acute kidney injury, ARF6

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APA

Lu, X., Jiang, G., Gao, Y., Chen, Q., Sun, S., Mao, W., Zhang, N., Zhu, Z., Wang, D., Zhang, G., Chen, M., Zhang, L., Chen, S. (2023). Platelet-derived extracellular vesicles aggravate septic acute kidney injury via delivering ARF6. International Journal of Biological Sciences, 19(16), 5055-5073. https://doi.org/10.7150/ijbs.87165.

ACS

Lu, X.; Jiang, G.; Gao, Y.; Chen, Q.; Sun, S.; Mao, W.; Zhang, N.; Zhu, Z.; Wang, D.; Zhang, G.; Chen, M.; Zhang, L.; Chen, S. Platelet-derived extracellular vesicles aggravate septic acute kidney injury via delivering ARF6. Int. J. Biol. Sci. 2023, 19 (16), 5055-5073. DOI: 10.7150/ijbs.87165.

NLM

CSE

Lu X, Jiang G, Gao Y, Chen Q, Sun S, Mao W, Zhang N, Zhu Z, Wang D, Zhang G, Chen M, Zhang L, Chen S. 2023. Platelet-derived extracellular vesicles aggravate septic acute kidney injury via delivering ARF6. Int J Biol Sci. 19(16):5055-5073.

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