TY - JOUR T1 - The Protective Effects of Receptor-Interactive Protein Kinase-3 Inhibitor - Dabrafenib on Cisplatin Induced Nephrotoxicity TT - Reseptör Etkileşimli Protein Kinaz-3 Inhibitörü Dabrafenib’in Sisplatin Nefrotoksisitesi Üzerine Koruyucu Etkileri1 AU - Küçüköner, Mehmet AU - Erdoğmuş Özgen, Zeynep AU - Aktar, Fesih AU - Alabalık, Ulas AU - Kaya, Meryem Şeyda AU - Erdinç, Levent AU - Kelle, İlker AU - Erdinç, Meral PY - 2025 DA - September Y2 - 2025 DO - 10.5798/dicletip.1785013 JF - Dicle Medical Journal JO - diclemedj PB - Dicle Üniversitesi WT - DergiPark SN - 1300-2945 SP - 507 EP - 515 VL - 52 IS - 3 LA - en AB - Objective: The aim of this study is to investigate the protective effects of dabrafenib, a receptor-interacting kinase-3 enzyme inhibitor, against necroptosis which has an important role in Cisplatin-induced nephrotoxicity.Methods: 32 male Sprague-Dawley rats were divided into 4 groups. A single dose of i.p. saline was given to the first group. In the second group, a single dose of cisplatin (5 mg/kg i.p.) was given. In the third group, 10mg/kg i.p injections of Dabrafenib began a day before injection of a single dose of 5 mg/kg, i.p. cisplatin for 7 days. In the forth group 10mg/kg Dabrafnib was injected i.p. for 7 days. After 7 days, in all groups rats were anesthetized and with a laparotomy left kidneys were isolated. Histopathological examinations, Western-Blot analyses (expression levels of RIP1, RIP3, and MLKL proteins), and malondialdehyde (MDA) measurements were performed on the isolated kidney tissuesResults: In the biochemical evaluation of the study, it was observed that MDA levels in the kidney tissue increased significantly in the Cisplatin group compared to the control group (p KW - Cisplatin KW - Nephrotoxicity KW - Dabrafenib N2 - Amaç: Bu çalışma reseptör etkileşimli kinaz-3 enzim inhibitörü olan dabrafenibin sisplatin tarafından tetiklenen nefrotoksisitede oluşan nekroptoza karşı koruyucu etkilerini araştırmaktır.Yöntemler: 32 adet Sprague-Dawley cinsi erkek rat 4 gruba ayrıldı. 1.gruba tek doz i.p. salin verildi. 2.gruba 5 mg/kg tek doz sisplatin i.p. olarak verildi. 3.gruba tek doz sisplatin (5 mg/kg,i.p) enjeksiyonundan bir gün önce başlanarak 7 gün boyunca Dabrafenib günde 10 mg/kg,i.p olarak verildi. 4. Gruba 7 gün boyunca Dabrafenib günde 10 mg/kg, i.p olarak verildi. Tüm gruplarda 7. Günün sonunda anestezi altında laparotomi yapılarak börekler izole edildi. Alınan böbrek dokularında histopatolojik incelemeler, Western-Blot analizleri (RIP1, RIP3, ve MLKL proteinlerinin ekspresyon seviyeleri) ve malondialdehit (MDA) ölçümler yapıldı.Bulgular: Çalışmada MDA düzeyleri değerlendirildiğinde, sisplatin uygulanan grupta kontrol grubuna kıyasla böbrek dokusundaki MDA düzeylerinin anlamlı düzeyde arttığı gözlendi (p CR - 1.Tang C, Livingston MJ, Safirstein R, Dong Z.Cisplatin nephrotoxicity: new insights andtherapeutic implications. Nat Rev Nephrol. 2023Jan;19(1):53–72. CR - 2.Manohar S, Leung N. Cisplatin nephrotoxicity: areview of the literature. J Nephrol. 2018Feb;31(1):15–25. CR - 3.Zhu S, Pabla N, Tang C, He L, Dong Z. DNA damageresponse in cisplatin-induced nephrotoxicity. ArchToxicol. 2015 Dec;89(12):2197–205. CR - 4.Alassaf N, Attia H. Autophagy and necroptosis incisplatin-induced acute kidney injury: Recentadvances regarding their role and therapeuticpotential. Front Pharmacol. 2023 Jan30;14:1103062. CR - 5.Linkermann A. Nonapoptotic cell death in acutekidney injury and transplantation. Kidney Int. 2016Jan;89(1):46–57. CR - 6.Shan B, Pan H, Najafov A, Yuan J. Necroptosis indevelopment and diseases. Genes Dev. 2018 Mar1;32(5–6):327–40. CR - 7.Dhuriya YK, Sharma D. Necroptosis: a regulatedinflammatory mode of cell death. Journal ofNeuroinflammation. 2018 Jul 6;15(1):199. CR - 8.Vandenabeele P, Galluzzi L, Vanden Berghe T,Kroemer G. Molecular mechanisms of necroptosis:an ordered cellular explosion. Nat Rev Mol Cell Biol.2010 Oct;11(10):700–14. CR - 9.Zhou W, Yuan J. Necroptosis in health anddiseases. Semin Cell Dev Biol. 2014 Nov;35:14–23. CR - 10.Li JX, Feng JM, Wang Y, et al. The B-Raf(V600E)inhibitor dabrafenib selectively inhibits RIP3 andalleviates acetaminophen-induced liver injury. CellDeath Dis. 2014 Jun 5;5(6):e1278. CR - 11.Pushpan CK, Kresock DF, Ingersoll MA, et al.Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI. J Am Soc Nephrol. 2024 Jan 1;35(1):22–40. CR - 12.Ingersoll MA, Lutze RD, Pushpan CK, et al.Dabrafenib protects from cisplatin-induced hearingloss in a clinically relevant mouse model. JCI Insight[Internet]. 2023 Dec 22 [cited 2025 Jun 16];8(24).Available from:https://insight.jci.org/articles/view/171140 CR - 13.Jennette JC, Olson JL, Silva FG, et al.ResearchGate. [cited 2025 Jun 24]. Scoring systemfor renal histopathology. Available from:https://www.researchgate.net/figure/Scoring-system-for-renal-histopathology_tbl1_342423429 CR - 14.Yao X, Panichpisal K, Kurtzman N, Nugent K.Cisplatin nephrotoxicity: a review. Am J Med Sci.2007 Aug;334(2):115–24. CR - 15.Kolbrink B, von Samson-Himmelstjerna FA,Murphy JM, Krautwald S. Role of necroptosis inkidney health and disease. Nat Rev Nephrol. 2023May;19(5):300–14. CR - 16.Choi ME, Price DR, Ryter SW, Choi AMK.Necroptosis: a crucial pathogenic mediator ofhuman disease. JCI Insight. 2019 Aug8;4(15):e128834, 128834. CR - 17.Xu Y, Ma H, Shao J, et al. A Role for TubularNecroptosis in Cisplatin-Induced AKI. J Am SocNephrol. 2015 Nov;26(11):2647–58. CR - 18.Wang JN, Liu MM, Wang F, et al. RIPK1 inhibitorCpd-71 attenuates renal dysfunction in cisplatin-treated mice via attenuating necroptosis,inflammation and oxidative stress. Clin Sci (Lond).2019 Jul 31;133(14):1609–27. CR - 19.Shi Y, Huang C, Zhao Y, et al. RIPK3 blockadeattenuates tubulointerstitial fibrosis in a mousemodel of diabetic nephropathy. Sci Rep. 2020 Jun26;10(1):10458. CR - 20.Lee JE, Kim JY, Leem J. Efficacy of Trametinib inAlleviating Cisplatin-Induced Acute Kidney Injury:Inhibition of Inflammation, Oxidative Stress, andTubular Cell Death in a Mouse Model. Molecules.2024 Jan;29(12):2881. UR - https://doi.org/10.5798/dicletip.1785013 L1 - https://dergipark.org.tr/tr/download/article-file/5246120 ER -