Platelet-derived extracellular vesicles aggravate septic acute kidney injury via delivering ARF6
Xun Lu, Guiya Jiang, Yue Gao, Qi Chen, Si Sun, Weipu Mao, Nieke Zhang, Zepeng Zhu, Dong Wang, Guangyuan Zhang, Ming Chen, Lei Zhang, Shuqiu Chen
Abstract
. 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.