Platelet-derived Extracellular Vesicles Aggravate Septic Acute Kidney Injury Via Delivering ARF6

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2023 Nov 6

PMID 37928258

Authors

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

Affiliations

Soon will be listed here.

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 or LPS-stimulated renal tubular epithelial cells (RTECs) . 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.

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