<br>成纤维细胞网状细胞衍生的外泌体是治疗脓毒症急性肾损伤的一种有前途的治疗方法,Kidney International

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成纤维细胞网状细胞衍生的外泌体是治疗脓毒症急性肾损伤的一种有前途的治疗方法
Kidney International ( IF 14.8 ) Pub Date : 2023-12-30 , DOI: 10.1016/j.kint.2023.12.007
Yiming Li ₁ , Chang Hu ₁ , Pan Zhai ₂ , Jing Zhang ₁ , Jun Jiang ₁ , Jinmeng Suo ₃ , Bo Hu ₁ , Jing Wang ₁ , Xiaocheng Weng ₄ , Xiang Zhou ₄ , Timothy R Billiar ₅ , John A Kellum ₆ , Meihong Deng ₇ , Zhiyong Peng ₈

Affiliation

Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China; Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China.
Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, China.
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, USA.
Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China; Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Intensive Care Unit of the second affiliated Hospital of Hainan Medical College, Haikou, Hainan, China.

脓毒症引起的急性肾损伤（S-AKI）具有高度致死性，有效的治疗药物稀缺。此前，我们报道了成纤维细胞网状细胞（FRC）对脓毒症的强大治疗功效。在这里，我们证明了 FRC 衍生的外泌体 (FRC-Exos) 在盲肠结扎和穿刺引起的脓毒症后改善 C57BL/6 小鼠肾功能的能力。成像证实 FRC-Exos 归巢于受损的肾脏。对 FRC-Exo 处理的原代肾小管细胞 (PKTC) 的 RNA-Seq 分析表明，FRC-Exo 在脂多糖 (LPS) 存在的情况下影响 PKTC 的命运。 FRC-Exos 在 LPS 刺激的 PKTC 中促进激酶 PINK1 依赖性线粒体自噬并抑制 NLRP3 炎性体激活。为了剖析 Exos 在 S-AKI 中的保护作用背后的机制，我们通过质谱法检查了 Exos 内的蛋白质，发现与巨噬细胞衍生的 Exos 相比，CD5L 是 FRC-Exos 中上调最多的蛋白质。重组 CD5L 治疗可减轻 LPS 刺激后肾细胞肿胀和表面气泡形成。 FRC 用 CD5L 慢病毒感染，以增加 FRC-Exos 中的 CD5L 水平，然后用肾小管细胞靶向肽 LTH 进行修饰，LTH 是一种与受损肾小管细胞上表达的生物标志物蛋白肾损伤分子-1 结合的肽，以增强结合特异性。与同等剂量的重组CD5L相比，修饰后的富含CD5L的FRC-Exos选择性结合PKTC，促进激酶PINK-泛素连接酶Parkin介导的线粒体自噬，抑制细胞焦亡，并通过阻碍NLRP3炎性体激活改善肾功能，从而提高脓毒症生存率。因此，修改 FRC-Exos 的策略可能是开发抗肾损伤疗法的新途径。

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Fibroblastic reticular cell-derived exosomes are a promising therapeutic approach for septic acute kidney injury

Sepsis-induced acute kidney injury (S-AKI) is highly lethal, and effective drugs for treatment are scarce. Previously, we reported the robust therapeutic efficacy of fibroblastic reticular cells (FRCs) in sepsis. Here, we demonstrate the ability of FRC-derived exosomes (FRC-Exos) to improve C57BL/6 mouse kidney function following cecal ligation and puncture-induced sepsis. imaging confirmed that FRC-Exos homed to injured kidneys. RNA-Seq analysis of FRC-Exo-treated primary kidney tubular cells (PKTCs) revealed that FRC-Exos influenced PKTC fate in the presence of lipopolysaccharide (LPS). FRC-Exos promoted kinase PINK1-dependent mitophagy and inhibited NLRP3 inflammasome activation in LPS-stimulated PKTCs. To dissect the mechanism underlying the protective role of Exos in S-AKI, we examined the proteins within Exos by mass spectrometry and found that CD5L was the most upregulated protein in FRC-Exos compared to macrophage-derived Exos. Recombinant CD5L treatment attenuated kidney cell swelling and surface bubble formation after LPS stimulation. FRCs were infected with a CD5L lentivirus to increase CD5L levels in FRC-Exos, which were then modified with the kidney tubular cell targeting peptide LTH, a peptide that binds to the biomarker protein kidney injury molecule-1 expressed on injured tubule cells, to enhance binding specificity. Compared with an equivalent dose of recombinant CD5L, the modified CD5L-enriched FRC-Exos selectively bound PKTCs, promoted kinase PINK-ubiquitin ligase Parkin-mediated mitophagy, inhibiting pyroptosis and improved kidney function by hindering NLRP3 inflammasome activation, thereby improving the sepsis survival rate. Thus, strategies to modify FRC-Exos could be a new avenue in developing therapeutics against kidney injury.

更新日期：2023-12-30

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