Investigation of the protective effects of Dabrafenib, receptor interacting protein kinase-3 inhibitor, against acute tubular necrosis due to colistin nephrotoxicity

Aim: The aim of this study was to investigate the protective effects of dabrafenib (Dab), a selective receptor-interacting kinase (RIP)3 enzyme inhibitor, against necroptosis induced by colistin-induced nephrotoxicity. Material and Method: 48 male Sprague-Dawley rats were examined in six groups. Three-day intraperitoneal (IP) drug administration was performed. The control group received 1 ml of saline daily and the second group received 10 mg/kg colistin (IP). The third and fourth groups received 10 mg/kg colistin (IP) and 10 mg/kg dabrafenib (IP) and 1.65 mg/kg necrostatin (IP), respectively. The fifth and sixth groups received 10 mg/kg dabrafenib (IP) and 1.65 mg/kg necrostatin (IP), respectively. After three days of administration, the kidneys were isolated from the rats of all groups by laparotomy under anesthesia. Right kidneys were separated for histopathologic examinations, Western-Blot analyses (expression levels of RIP3, CaMKII, CypD proteins) and malondialdehyde (MDA) measurements. Perfusion pressures of the left kidneys were measured and serum urea and creatinine levels were determined from blood samples obtained from rats via cardiac access. Results: Dabrafenib administration significantly decreased renal perfusion pressure, urea, creatinine levels, MDA levels and expression levels of necroptotic proteins in the colistin group (p<0.05). Furthermore, when the protective effects of dabrafenib and necrostatin were compared, dabrafenib was found to be significantly more protective against necroptosis (p<0.05). Conclusion: Dabrafenib showed a protective effect against necroptosis in colistin-induced nephrotoxic injury, while dabrafenib was found to be more protective than Necrostatin, which has been proven to be protective in previous studies.