RIPK1/RIPK3/MLKL Necrosome Contributes to the Sepsis-Induced Cardiorenal Necroptotic Inflammatory Injury and Mortality.

Bahar Tunctan, Muhammed Ahmed-Reda Elosman, Sefika Pinar Senol, Elif Ikiz, Tuba Kara
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Abstract

Introduction: Due to its critical role in inflammation and necroptotic cell death, RIPK1 has been considered a prominent therapeutic drug target for managing a wide variety of diseases, including sepsis. Therefore, we aimed to investigate whether the RIPK1-driven necroptotic pathway contributes to the nitrosative stress-mediated cardiorenal inflammatory necroptotic injury and mortality using RIPK1 inhibitor, Nec-1s, in the murine sepsis model induced by LPS.

Methods: Experiments were performed using mice injected intraperitoneally with DMSO or Nec-1s with saline and/or LPS. Following euthanasia and 6 hours after the injection of these agents, arteriovenous blood samples, hearts, and kidneys of the animals were collected. Serum MPO, iNOS, CKMB, creatinine, and HMGB1 levels were measured by ELISA. Associated proteins were measured by immunoblotting. H&E staining was used to evaluate histopathological changes in the tissues. In the mortality studies, the mice were monitored every 6 hours for mortality up to 96 hours after saline, LPS, DMSO, and/or Nec-1s injection.

Results: In the LPS-injected mice, a rise in serum MPO, iNOS, CK-MB, creatinine, and HMGB1 levels was associated with the enhanced expression/activity of RIPK1/RIPK3/MLKL necrosome, HMGB1, iNOS, nitrotyrosine, gp91phox, and p47phox, in addition to scores related to histopathological changes in their tissues. Nec-1s attenuated the LPS-induced changes. Mortality rates of 10%, 50%, and 60% were observed at the 24th, 36th, and 48th hours, respectively, in the LPS-treated mice. When endotoxemic mice were treated with Nec-1s, mortality rates were 60%, 90%, and 100% at 18, 30, and 42 hours, respectively.

Conclusion: These findings suggest that RIPK1/RIPK3/MLKL necrosome contributes to not only LPS-induced nitrosative stress-mediated cardiorenal inflammatory necroptotic injury, but also mortality.

RIPK1/RIPK3/MLKL坏死体参与败血症诱导的心肾坏死性炎症损伤和死亡
由于其在炎症和坏死细胞死亡中的关键作用,RIPK1已被认为是治疗包括脓毒症在内的多种疾病的重要治疗药物靶点。因此,我们旨在利用RIPK1抑制剂nec -1在LPS诱导的小鼠脓毒症模型中研究RIPK1驱动的坏死性坏死通路是否参与亚硝化应激介导的心肾炎症性坏死性损伤和死亡。方法:小鼠腹腔注射DMSO或nec -1,并注射生理盐水和/或LPS。安乐死后及注射后6小时,取动物动静脉血、心脏、肾脏标本。ELISA法检测血清MPO、iNOS、CKMB、肌酐、HMGB1水平。免疫印迹法测定相关蛋白。H&E染色评价组织病理变化。在死亡率研究中,每隔6小时监测小鼠在生理盐水、LPS、DMSO和/或nec -1注射后的死亡率,直至96小时。结果:lps注射小鼠血清MPO、iNOS、CK-MB、肌酐和HMGB1水平升高与RIPK1/RIPK3/MLKL坏死体、HMGB1、iNOS、硝基酪氨酸、gp91phox、p47phox表达/活性增强有关,并与组织病理变化相关。nec -1可减弱lps诱导的变化。lps处理小鼠在第24、36和48小时的死亡率分别为10%、50%和60%。当内毒素小鼠用nec -1处理时,在18、30和42小时的死亡率分别为60%、90%和100%。结论:提示RIPK1/RIPK3/MLKL坏死体不仅参与lps诱导的亚硝化应激介导的心肾炎症性坏死损伤,而且参与死亡。
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