Intestinal barrier dysfunction is the initial and propagable factor of sepsis in which acute kidney injury (AKI) has been considered as a common life-threatening complication. Our recent study identifies the regulatory role of Pellino1 in tubular death under inflammatory conditions in vitro. The objective of our current study is to explore the impact of Pellino1 on gut-kidney axis during septic AKI and uncover the molecular mechanism (s) underlying this process. Immunohistochemistry (IHC) was conducted to evaluate Pellino1 and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels in renal biopsies from critically ill patients with a clinical diagnosis of sepsis. Functional and mechanistic studies were characterized in septic models of the -knockout () mice by histopathological staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunofluorescence, biochemical detection, CRISPR/Cas9-mediated gene editing and intestinal organoid. Pellino1, together with NLRP3, are highly expressed in renal biopsies from critically ill patients diagnosed with sepsis and kidney tissues of septic mice. The mice with sepsis become less prone to develop AKI and have markedly compromised NLRP3 activation in kidney. Loss of endows septic mice refractory to intestinal inflammation, barrier permeability and enterocyte apoptosis that requires stimulator of interferons genes (STING) pathway. Administration of STING agonist DMXAA deteriorates AKI and mortality of septic mice in the presence of kidney-specific NLRP3 reconstitution. Our studies suggest that Pellino1 has a principal role in orchestrating gut homeostasis towards renal pathophysiology, thus providing a potential therapeutic target for septic AKI.

中文翻译：

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Pellino1 通过激活 STING 通路和 NLRP3 炎性体协调肠肾轴，使脓毒性急性肾损伤永久化

肠屏障功能障碍是脓毒症的初始和传播因素，其中急性肾损伤（AKI）被认为是一种常见的危及生命的并发症。我们最近的研究确定了 Pellino1 在体外炎症条件下肾小管死亡中的调节作用。我们当前研究的目的是探讨脓毒症 AKI 期间 Pellino1 对肠肾轴的影响，并揭示该过程背后的分子机制。采用免疫组织化学 (IHC) 方法评估临床诊断为脓毒症的危重患者肾活检中 Pellino1 和 NOD 样受体热蛋白结构域相关蛋白 3 (NLRP3) 的水平。通过组织病理学染色、酶联免疫吸附测定 (ELISA)、流式细胞术、免疫荧光、生化检测、CRISPR/Cas9 介导的基因编辑和肠道类器官，在敲除小鼠脓毒症模型中进行功能和机制研究。 Pellino1 与 NLRP3 在诊断为脓毒症的危重患者的肾活检和脓毒症小鼠的肾组织中高表达。患有脓毒症的小鼠不太容易发生 AKI，并且肾脏中 NLRP3 的激活明显受损。败血症小鼠的损失使它们难以抵抗肠道炎症、屏障通透性和肠细胞凋亡，需要干扰素基因刺激剂（STING）途径。在肾脏特异性 NLRP3 重建存在的情况下，给予 STING 激动剂 DMXAA 会恶化脓毒症小鼠的 AKI 和死亡率。我们的研究表明，Pellino1 在协调肠道稳态以实现肾脏病理生理学方面发挥着重要作用，从而为脓毒症 AKI 提供了潜在的治疗靶点。