Targeting the PANoptosome Using Necrostatin-1 Reduces PANoptosis and Protects the Kidney Against Ischemia-Reperfusion Injury in a Rat Model of Controlled Experimental Nonheart-Beating Donor

IF 0.8 4区医学 Q4 IMMUNOLOGY

Transplantation proceedings Pub Date : 2024-12-01 DOI:10.1016/j.transproceed.2024.10.047

Mehmet Dokur , Erdal Uysal , Faruk Kucukdurmaz , Serdar Altinay , Sait Polat , Kadir Batcioglu , Yakup Yilmaztekin , Turkan Guney , Tugce Sapmaz Ercakalli , Asli Yaylali , Efe Sezgin , Zafer Cetin , Eyup Ilker Saygili , Osman Barut , Hatem Kazimoglu , Gokturk Maralcan , Suna Koc , Mehmet Sokucu , Sema Nur Dokur Yeni

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引用次数: 0

Abstract

Purpose

Reducing renal ischemia is crucial for the function and survival of grafts from nonheartbeat donors, as it leads to inflammatory responses and tubulointerstitial damage. The primary concern with organs from nonheartbeat donors is the long warm ischemia period and reperfusion injury following renal transplantation. This study had two main goals; one goal is to determine how Necrostatin-1 targeting the PANoptosome affects PANoptosis in the nonheart-beating donor rat model. The other goal is to find out if Necrostatin-1 can protect the kidney from ischemic injury for renal transplantation surgery.

Methods

Twenty-four rats were grouped randomly as control and Necrostatin-1 in this experimental animal study, and we administered 1.65 mg/kg of Necrostatin-1 intraperitoneally to the experimental group for 30 minutes before cardiac arrest. We removed the rats’ left kidneys and measured various oxidative stress marker measures such as malondialdehyde, superoxide dismutase, catalase, GPx, and 8-hydroxy-2-deoxyguanosine levels. We then subjected the tissues to immunohistochemical analysis, electron microscopy, and histopathological analysis.

Findings

The Necrostatin-1 group had a lower total tubular injury score (P < .001) and less Caspase-3, gasdermin D, and mixed lineage kinase domain-like protein expression. Additionally, the apoptotic index of the study group was lower (P < .001). Furthermore, the study group had higher levels of superoxide dismutase and GPx (P < .05), whereas malondialdehyde levels were reduced (P = .009). Electron microscopy also revealed a significant improvement in tissue structure in the Necrostatin-1 group.

Conclusion

Necrostatin-1 protects against ischemic acute kidney injury in nonheart-beating donor rats by inhibiting PANoptosis via the blockade of RIPK1. As a result of this, Necrostatin-1 may offer novel opportunities for protecting donor kidneys from renal ischemia-reperfusion injury during transplantation in patients with end-stage kidney disease requiring a renal transplantation.

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用坏死他汀-1靶向PANoptosome减轻PANoptosis并保护肾脏免受缺血-再灌注损伤

目的：减少肾缺血对非心跳供体移植的功能和存活至关重要，因为它会导致炎症反应和小管间质损伤。非心跳供体器官的主要问题是肾移植后的长时间热缺血和再灌注损伤。这项研究有两个主要目标；目的之一是确定坏死他汀-1靶向PANoptosome如何影响无心脏跳动供体大鼠模型的PANoptosis。另一个目标是发现坏死他汀-1是否可以在肾移植手术中保护肾脏免受缺血性损伤。方法：将24只大鼠随机分为对照组和坏死性他汀-1，实验组在心脏骤停前30分钟腹腔注射1.65 mg/kg坏死性他汀-1。我们切除了大鼠的左肾，测量了各种氧化应激标志物，如丙二醛、超氧化物歧化酶、过氧化氢酶、GPx和8-羟基-2-脱氧鸟苷水平。然后我们对这些组织进行免疫组织化学分析、电子显微镜和组织病理学分析。结果：坏死他汀-1组总小管损伤评分较低（P < 0.001）， Caspase-3、gasdermin D和混合谱系激酶结构域样蛋白表达较低。研究组细胞凋亡指数明显低于对照组（P < 0.001）。此外，研究组的超氧化物歧化酶和GPx水平较高（P < 0.05），而丙二醛水平降低（P = 0.009）。电镜也显示坏死他汀-1组的组织结构有显著改善。结论：坏死他汀-1通过阻断RIPK1抑制PANoptosis，对非心脏跳动供体大鼠缺血性急性肾损伤具有保护作用。因此，对于需要肾移植的终末期肾病患者，坏死他汀-1可能为在移植过程中保护供肾免受肾缺血-再灌注损伤提供了新的机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Transplantation proceedings 医学-免疫学

CiteScore

1.70

自引率

0.00%

发文量

502

审稿时长

60 days

期刊介绍： Transplantation Proceedings publishes several different categories of manuscripts, all of which undergo extensive peer review by recognized authorities in the field prior to their acceptance for publication. The first type of manuscripts consists of sets of papers providing an in-depth expression of the current state of the art in various rapidly developing components of world transplantation biology and medicine. These manuscripts emanate from congresses of the affiliated transplantation societies, from Symposia sponsored by the Societies, as well as special Conferences and Workshops covering related topics. Transplantation Proceedings also publishes several special sections including publication of Clinical Transplantation Proceedings, being rapid original contributions of preclinical and clinical experiences. These manuscripts undergo review by members of the Editorial Board. Original basic or clinical science articles, clinical trials and case studies can be submitted to the journal?s open access companion title Transplantation Reports.