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    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
    (Elsevier Science Inc, 2024) Dokur, Mehmet; Uysal, Erdal; Kucukdurmaz, Faruk; Altinay, Serdar; Polat, Sait; Batcioglu, Kadir; Yilmaztekin, Yakup
    Purpose. Reducing renal ischemia is crucial for the function and survival of grafts from non- heartbeat 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 nonheartbeating donor rat model. The other goal is to fi nd 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, Necrostatin1 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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    Targeting the PANoptosome with 3,4-Methylenedioxy-?-Nitrostyrene, Reduces PANoptosis and Protects the Kidney against Renal Ischemia-Reperfusion Injury
    (Taylor & Francis Inc, 2022) Uysal, Erdal; Dokur, Mehmet; Kucukdurmaz, Faruk; Altinay, Serdar; Polat, Sait; Batcioglu, Kadir; Sezgin, Efe
    Objectives: The objectives of this study were a) to investigate the effect of targeting the PANoptosome with 3,4-methylenedioxy-beta-nitrostyrene (MNS) on PANoptosis in the Renal ischemia-reperfussion (RIR) model b) to investigate the kidney protective effect of MNS toward RIR injury. Methods: Thirty-two rats were divided into four groups randomly. The groups were assigned as Control, Sham, DMSO (dimethyl sulfoxide) and MNS groups. The rats in the MNS group were intraperitoneally given 20 mg/kg of MNS 30 minutes before reperfusion. 2% DMSO solvent that dissolves MNS were given to the rats in DMSO group. Left nephrectomy was performed on the rats under anesthesia at the 6th hour after reperfusion. Glutathione peroxidase (GPx), malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) and 8-Okso-2'-deoksiguanozin (8-OHdG) levels were measured. Immunohistochemical analysis, electron microscopic and histological examinations were carried out in the tissues. Results: Total tubular injury score was lower in the MNS group (p < 0.001). Caspase-3, Gasdermin D and MLK (Mixed Lineage Kinase Domain Like Pseudokinase) expressions were considerably decreased in the MNS group (p < 0.001). Apoptotic index (AI) was found to be low in the MNS group (p < 0.001). CAT and SOD levels were higher in the MNS Group (p = 0.006, p = 0.0004, respectively). GPx, MDA, and 8-OH-dG levels were similar (p > 0.05) in all groups. MNS considerably improved the tissue structure, based on the electron microscopic analysis. Conclusions: Our results suggested that MNS administrated before the reperfusion reduces pyroptosis, apoptosis and necroptosis. These findings suggest that MNS significantly protects the kidney against RIR injury by reducing PANoptosis as a result of specific inhibition of Nod-like receptor pyrin domain-containing 3 (NLRP 3), one of the PANoptosome proteins.