Investigation of epigenetic mechanisms involved in diabetic kidney disease

• Grant number: 20/12114-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2020
• End date: December 31, 2021
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Karina Thieme
• Grantee: Maria Luiza Ribeiro Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/00573-4 - The role of DNA (hydroxy)methylation in podocytes dysfunction: epigenetic perspectives for the treatment of Chronic Kidney Disease, AP.JP

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Type 1 and type 2 diabetes lead to the development of DKD, however, the growth in the number of individuals with obesity and type 2 diabetes has been a major contributor to the increase in the prevalence, incidence and number of deaths from chronic kidney disease. The understanding of the mechanisms that produce the constellation of morphological and functional changes that occur in humans is still very incomplete. Therefore, the use of experimental models that resemble the course of the disease in humans is necessary. New studies have shown that epigenetic modifications contribute to the establishment and maintenance of cell identity and that disorders in these systems can lead to changes in gene expression and, consequently, the activation of harmful signaling pathways and a reduction in the expression of nephroprotective molecules. In particular, it is relevant to investigate the dynamic balance between the expression/activity of the enzymes responsible for DNA methylation, i.e., DNA methyl transferases (DNMT), and in the active demethylation, promoted by TET proteins. Thus, this study aims to expand the knowledge of the epigenetic mechanisms involved in the development and progression of DKD and intends to investigate the general hypothesis that epigenetic modifications are associated with changes in the expression of genes implicated in the development and/or progression of DKD. In this sense, the general objective of this project is to explore the epigenetic changes associated with fibrosis and renal dysfunction in BTBR ob/ob mice, an experimental model of diabetic kidney disease. BTBR mice are naturally insulin resistant and, when associated with the ob/ob mutation, exhibit sustained hyperglycemia and develop extreme obesity and progressive hypertriglyceridemia, along with the development of microvascular complications of diabetes in a manner similar to what occurs in humans. This is currently considered the best murine model for the study of DKD. The proposal will have an exploratory approach that will evaluate gene expression (RT-qPCR) and protein (immunostaining and immunoblotting) of the epigenetic enzymes DNMT and TET, as well as relevant signaling pathways for renal injury. With the results of this study, we seek to understand the molecular mechanisms underlying the development and progression of DKD, which will open the way for new therapeutic strategies. (AU)