The effects of esculin treatment on mitochondrial dynamics and epigenetics at the Experimental Diabetic Nephropathy early phase

• Grant number: 22/01263-4
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2023
• End date: May 31, 2025
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Elisa Mieko Suemitsu Higa
• Grantee: Elisa Mieko Suemitsu Higa
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Elizabeth Suchi Chen ; Leticia Prates Roma ; Lucas Ferres ; Robson Souza Serralha ; Steen Larsen

Abstract

Diabetes mellitus (DM) is a chronic disease that can evolve, leading to the emergence of comorbidities, such as diabetic nephropathy. The main characteristic of DM, hyperglycemia, is considered responsible for causing mitochondrial changes, such as a reduction in ATP synthesis, an increase in the production of reactive oxygen species, and the activation of pathways that culminate in cell death. Disturbances in the cellular microenvironment activate epigenetic mechanisms, promoting changes in gene expression without altering the DNA sequence. In a previous study in our laboratory, we showed that treatment with esculin restored mitochondrial function in the kidney of diabetic animals. Objective: This work aims to evaluate whether the improvement of mitochondrial function after treatment with esculin is due to modulations in the mitochondrial dynamics and/or by interference in the epigenetic alterations of the mitochondrial DNA, which would result in the dysfunction of this organelle. Methodology: Male Wistar rats at 7 weeks of age will be uninefrectomized. At 8 weeks of age, DM will be induced by streptozotocin (60 mg/kg; IV). Control and diabetic animals will be treated with daily doses of esculin hydrate (50 mg/kg; p.o.) for 8 weeks. At the end of the protocol, the animals will be euthanized and the remaining kidney will be collected to evaluate the mitochondrial dynamics using Western blotting, immunohistochemistry, and transmission electron microscopy techniques. We will also sequence mitochondrial DNA to assess methylation levels. The results will be described as mean ± SE; with significance for p <0.05, where we used the GraphPad Prism 6.0 software. (AU)