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Effect of annexin A1 mimetic peptide on hepatic and renal toxicity induced by cisplatin in rats

Grant number: 19/14331-5
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): September 01, 2019
Effective date (End): October 31, 2021
Field of knowledge:Biological Sciences - Morphology - Histology
Principal researcher:Cristiane Damas Gil
Grantee:Danilo Bancalero Mendonça Lucchi
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Cisplatin is a widely used antineoplastic agent and is related to nephrotoxicity and hepatotoxicity. Oxidative stress is a very common mechanism in the cytotoxicity of cisplatin. The formation of reactive oxygen species (ROS) induced by cisplatin is responsible for lipid peroxidation, depletion of sulfhydryl groups, alteration of different signal transduction pathways, among other actions, that can cause DNA damage and, consequently, cell apoptosis. In this context, we highlight annexin A1 (AnxA1), 37 kDa protein which, in addition to mediating inflammation, is involved in important roles including proliferation, differentiation and apoptosis. In addition, cell glandular epithelial cells revealed a protective role of AnxA1 in DNA damage. It is also important to note that the regulatory action of AnxA1 and its mimetic peptides is mediated by formyl peptide receptors (Fprs) that belong to a class of G protein-coupled transmembrane receptors. However, the role of AnxA1 and its Fprs in the cisplatin-induced toxicity in kidney and liver have been poorly explored. In this study, we will evaluate the effect of with the Ac2-26, a mimetic peptide of AnxA1, in the renal and hepatic toxicity induced by cisplatin in Wistar rats. The animals will be divided into three groups (n = 5 animals): Cis - will receive intraperitoneally three doses of cisplatin (10 mg / kg) per day, totaling one treatment of 30 mg/kg in 3 days; Ac2-26 - will receive pharmacological treatment intraperitoneally with 1 mg/kg of Ac2-26, 15 minutes prior to administration of cisplatin (3 days); SHAM (control) - will receive vehicle (sterile saline) alone. After 6 hours of the last dose of cisplatin or vehicle, the animals will be euthanized for the following analyzes: (I) quantification of blood leukocytes; II) histological examination of the kidney and liver; III) expression of Fpr1 and Fpr2 in the kidney and liver by immunohistochemistry; IV) expression of AnxA1 and caspase 3 cleaved by western blotting. The results will contribute to the knowledge of the cellular and molecular mechanisms that involve the biological actions of AnxA1 in nephrotoxicity and hepatotoxicity, as well as possible therapeutic targets for the deleterious effects of cisplatin.

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