Analysis of Sirtuin 1 activation in restoring autophagy in podocytes

• Grant number: 20/15557-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2021
• End date: June 30, 2022
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Karina Thieme
• Grantee: Ana Paula Malavolta Luz
• 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 kidney disease in the world. Currently, treatments are mainly based on blood glucose and blood pressure control, but clinical studies suggest that they have a mild or neutral positive effect on the progression of DKD once renal dysfunction has already been established. Hyperglycemia, one of the main supporting elements in the development of DKD, can lead to the dysfunction of several cell types and consequently failure in renal function and elimination of proteins in the urine, especially albumin. Among the most affected cells are podocytes, highly differentiated cells, which do not replicate and that together with endothelial cells, are responsible for maintaining the glomerular filtration barrier. Autophagy, a cell recycling process, is very important for the proper functioning of podocytes. The expression of Sirtuin 1, an enzyme of the NAD-dependent histone deacetylase family, has several nephroprotective effects that include the maintenance of cellular cytoarchitecture, anti-fibrotic and anti-oxidative effects, as well as the regulation of energy metabolism and autophagy. In addition, it is known that the expression of SIRT1 is decreased in DKD, which could be associated with cellular dysfunction. Thus, this proposal aims to study whether the specific activation of SIRT 1 can assist in restoring autophagy and the function of podocytes exposed to high glucose. Using an in vitro approach, cultured human podocytes will be exposed to high glucose and/or SIRT1 activator (SRT1720). The effects of SIRT1 activation will be studied on: a) the expression of genes and proteins that are markers of podocyte differentiation and autophagy; b) cellular permeability to albumin. We hope with the results of this study to elucidate new mechanisms that can prevent podocyte dysfunction and thus contribute to the search for therapeutic strategies that improve the progression of DKD.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PEREIRA, BEATRIZ MARIA VELOSO; DE PONTE, MARIANA CHARLEAUX; LUZ, ANA PAULA MALAVOLTA; THIEME, KARINA. DNA methylation enzymes in the kidneys of male and female BTBR ob/ob mice. FRONTIERS IN ENDOCRINOLOGY, v. 14, p. 10-pg., 2023-04-05. (19/10583-0, 18/00573-4, 21/12782-0, 20/15557-4)