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

• Published in: Transplantation proceedings 2024-12, Vol.56 (10), p.2268-2279
• Main Authors: Dokur, Mehmet, Uysal, Erdal, Kucukdurmaz, Faruk, Altinay, Serdar, Polat, Sait, Batcioglu, Kadir, Yilmaztekin, Yakup, Guney, Turkan, Sapmaz Ercakalli, Tugce, Yaylali, Asli, Sezgin, Efe, Cetin, Zafer, Saygili, Eyup Ilker, Barut, Osman, Kazimoglu, Hatem, Maralcan, Gokturk, Koc, Suna, Sokucu, Mehmet, Dokur Yeni, Sema Nur
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Imidazoles - pharmacology; Indoles - pharmacology; Kidney - blood supply; Kidney - drug effects; Kidney - pathology; Kidney Transplantation; Male; Necroptosis - drug effects; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control
• ISSN: 0041-1345; 1873-2623; 1873-2623
• DOI: 10.1016/j.transproceed.2024.10.047

•Renal ischemia-reperfusion injury often leads to delayed graft function and graft loss.•Recently, researchers discovered that the coordinated regulation of apoptosis, necroptosis, ferroptosis, and pyroptosis can create a novel route of programmed cell death, or PANoptosis, and the PANoptosome reduces the damage that ischemic changes of the kidneys.•Necrostatin-1, a specific inhibitor of RIPK1, has potential for use in the early stages of warm ischemia, reducing necroptosis caused by renal ischemia and reperfusion injury in nonheart-beating donor rats by inhibiting PANoptosis through the PANoptosome process.•Necrostatin-1 has potential as a therapeutic agent, offering novel opportunities for patients undergoing nonheart-beating kidney transplantation in the near future if prospective and advanced clinical and experimental studies confirm its neproprotective effect on renal tissue during renal ischemia-reperfusion. 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. 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. 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