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血小板衍生的细胞外囊泡通过传递 ARF6 加重脓毒症急性肾损伤。

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

机构信息

Department of Urology, Affiliated Zhongda hospital of Southeast University, Nanjing, China.

Surgical Research Center, Institute of Urology, School of Medicine, Southeast University, Nanjing, China.

出版信息

Int J Biol Sci. 2023 Oct 2;19(16):5055-5073. doi: 10.7150/ijbs.87165. eCollection 2023.

DOI:10.7150/ijbs.87165
PMID:37928258
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10620832/
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.

摘要

循环血浆细胞外囊泡（EVs）主要来源于血小板，并可能促进脓毒症中的器官功能障碍。然而，血小板衍生 EVs 在脓毒症诱导的急性肾损伤（AKI）中的作用仍知之甚少。本研究从用磷酸盐缓冲盐水（PBS）或脂多糖（LPS）处理的人血小板上清液中提取 EVs。然后，我们将 PBS-EVs 或 LPS-EVs 给予盲肠结扎和穿刺（CLP）小鼠或 LPS 刺激的肾小管上皮细胞（RTECs）。我们的结果表明，LPS-EVs 通过促进细胞凋亡、炎症和氧化应激加重脓毒症 AKI。此外，通过定量蛋白质组学分析发现，ADP-核糖基化因子 6（ARF6）是 PBS-EVs 和 LPS-EVs 之间的差异蛋白。在机制上，ARF6 通过激活 ERK/Smad3/p53 信号通路加重脓毒症诱导的 AKI。LPS 上调 RTECs 中的 ARF6 依赖于 TLR4/MyD88 通路。ARF6 的基因和药理学抑制均减轻了脓毒症 AKI。此外，血小板在脓毒症期间被 TLR4 及其下游介质 IKK 激活，控制血小板分泌。抑制血小板分泌可减轻脓毒症 AKI。总之，我们的研究表明，血小板衍生的 EVs 可能是脓毒症 AKI 的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee83/10620832/1e714dc8f0a6/ijbsv19p5055g012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee83/10620832/38cda2efb669/ijbsv19p5055g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee83/10620832/19c211047b41/ijbsv19p5055g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee83/10620832/49d742ec4b09/ijbsv19p5055g008.jpg
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本文引用的文献

[1]
NOX4 is a potential therapeutic target in septic acute kidney injury by inhibiting mitochondrial dysfunction and inflammation.

Theranostics. 2023

[2]
STING activation in platelets aggravates septic thrombosis by enhancing platelet activation and granule secretion.

Immunity. 2023-5-9

[3]
Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling.

Neuron. 2022-10-5

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The Pathophysiology of Sepsis-Associated AKI.

Clin J Am Soc Nephrol. 2022-7

[5]
Chronic aspirin use and survival following sepsis-A propensity-matched, observational cohort study.

Clin Microbiol Infect. 2022-9

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Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis.

Cell Death Dis. 2022-4-11

[7]
Honokiol ameliorates cisplatin-induced acute kidney injury via inhibition of mitochondrial fission.

Br J Pharmacol. 2022-7

[8]
Arf6 exacerbates allergic asthma through cell-to-cell transmission of ASC inflammasomes.

JCI Insight. 2021-8-23

[9]
Reduning injection and its effective constituent luteoloside protect against sepsis partly via inhibition of HMGB1/TLR4/NF-κB/MAPKs signaling pathways.

J Ethnopharmacol. 2021-4-24

[10]
Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance.

Theranostics. 2021

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