Influence of GLP-1 analog in nephrotoxicity-induced by doxorubicin in rats

• Grant number: 23/05947-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): July 01, 2023
• Effective date (End): June 30, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Marcos Ferreira Minicucci
• Grantee: Lara Pompiani Carreira
• Host Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Doxorubicin is one of the most effective and most used chemotherapy drugs in the world, but its use may be limited by its side effects, which include cardiotoxicity, hepatotoxicity, gastrointestinal tract toxicity, and nephrotoxicity. Nephrotoxicity is one of the most important complications, as it can occur in up to 60% of patients undergoing chemotherapy and most patients do not recover renal function after the installation of renal injury. The mechanisms involved in nephrotoxicity are not yet fully understood but involve increased oxidative stress, inflammation, and mitochondrial dysfunction, which culminate in the death of otherwise healthy cells. To date, there is no specific treatment that attenuates doxorubicin-induced kidney injury. Liraglutide is a GLP-1 analog that is nephroprotective in patients with risk factors for chronic kidney disease. In addition, it has an anti-inflammatory and antioxidant effect and may be a promising therapy in the attenuation of nephrotoxicity. Therefore, we aim to evaluate the protective effect of liraglutide against doxorubicin-induced nephrotoxicity in rats. For this purpose, kidney tissues collected from a project approved by the local Ethics Committee (CEUA-FMB 1400/2021) will be used, whose design was as follows: 60 male Wistar rats were allocated into 4 groups: control group (C), doxorubicin group (D ), liraglutide group (L) and doxorubicin + liraglutide group (DL). Animals in groups L and DL received a subcutaneous injection of liraglutide (GLP-1 analog) 0.6mg/kg of weight and groups C and D received an injection of 0.9% saline solution in an equivalent volume, daily, for 14 days. After 12 days of treatment with liraglutide or saline, the animals in groups D and DL received an intraperitoneal injection of doxorubicin 20 mg/kg of body weight, a single dose, and groups C and L received an injection of saline solution 0.9% in equivalent volume. After 48 hours of doxorubicin administration, the animals were euthanized, and the kidney tissue was collected and stored at -80°C. The tissue will be used to assess oxidative stress by quantifying the concentration of malondialdehyde and carbonyl proteins in renal tissue and the activity of the antioxidant enzymes catalase and superoxide dismutase by spectrophotometry. HO-1 proteins, total and phosphorylated NF-kB, TNF-±, Nrf-2, and PGC-1± proteins will also be quantified in the renal tissue by Western blot. Statistical analysis: 2-way ANOVA, with adopted statistical significance of 5% for all analyses.