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. 2024:17:e18761429374574.
doi: 10.2174/0118761429374574250415114715.

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

Bahar Tunctan  1 , Muhammed Ahmed-Reda Elosman  1 , Sefika Pinar Senol  2 , Elif Ikiz  1 , Tuba Kara  3
Affiliations

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

Bahar Tunctan et al. Curr Mol Pharmacol. 2024.

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.

Keywords: Lipopolysaccharide; Mortality.; Necroptosis; Nitrosative stress; Sepsis.

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