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Adaptive mechanisms of renal function in a model of adriamycin-induced nephrotoxicity: participation of sirtuin 1 and claudin-1

Grant number: 18/26528-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): May 01, 2019
Effective date (End): May 31, 2021
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal researcher:Maria Oliveira de Souza
Grantee:Guilherme Lopes Gonçalves
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The Focal Segmental Glomerulosclerosis (FSGS) is the leading cause of progression of Chronic Kidney Disease (CKD) and it’s responsible for the increasing number of cases of dialysis and kidney transplants worldwide. FSGS is characterized by presence of glomerular fibrosis, podocyte lesion and changes in tubular function, which results in severe proteinuria and consequent loss of renal function. Experimental models of FSGS are developed using nephrotoxic drugs such as adriamycin and are relevant, since they present similarities to human FSGS. Studies in experimental models of diabetes report renoprotective role of sirtuin 1 associated with repression on claudin-1 expression in podocytes and consequent reduction of proteinuria. In addition, recent studies highlight the relationship between renal insult, endoplasmic reticulum stress and autophagy processes as adaptive response or apoptosis in podocytes and tubular cells. The lack of knowledge about the mechanisms underlying the progression of FSGS associated with use of nephrotoxic drugs makes it difficult to develop therapeutic approaches with regard the prevention of proteinuria and progression of CKD. Our hypothesis is that in the adriamycin-induced FSGS model, proteinuria-associated podocyte injury is related to sustained endoplasmic reticulum stress and consequent decrease in autophagic response, reduction of sirtuin 1 expression, and increased expression of claudin-1, as well as increased apoptotic response. In this condition, SRT1720 (sirtuin 1 agonist) therapy may reduce the expression of claudin-1 and therefore attenuate renal injury by restoring the function of podocytes, which will contribute to improvement of proteinuria. Thus, the general objective of the proposal is to point out the mechanisms responsible for podocyte lesion on in vivo and in vitro models of FSGS in acute and chronic phases of the disease, investigating the involvement of sustained endoplasmic reticulum stress, sirtuin 1 and claudin-1 in this condition. The planned methodologies include western blotting and immunofluorescence to assess endoplasmic reticulum stress, apoptosis, autophagy, sirtuin 1 and claudin-1. In addition, we will also use in vitro approaches such as primary culture of podocytes and silencing of sirtuin 1 or claudin-1 for a comparison with animal model. The statistical analysis of the results will be performed by one-way ANOVA method and Bonferroni's post-test; p <0.05 will be considered significant in comparison to control or treated groups. Results will be presented as a mean ± standard error. (AU)

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)
LINS, BRUNA BEZERRA; CASARE, FERNANDO AUGUSTO MALAVAZZI; FONTENELE, FLAVIA FERREIRA; GONCALVES, GUILHERME LOPES; OLIVEIRA-SOUZA, MARIA. Long-Term Angiotensin II Infusion Induces Oxidative and Endoplasmic Reticulum Stress and Modulates Na+ Transporters Through the Nephron. FRONTIERS IN PHYSIOLOGY, v. 12, APR 1 2021. Web of Science Citations: 0.

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