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Mechanisms involved in the progression of renal diseases in experimental models of the adriamycin-induced nephrotoxicity or of the ischemia/reperfusion and diabetes

Grant number: 19/13584-7
Support type:Regular Research Grants
Duration: May 01, 2020 - April 30, 2022
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Maria Oliveira de Souza
Grantee:Maria Oliveira de Souza
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acute kidney injury (AKI) is one of the most common causes for the progression of chronic kidney disease (CKD) and consequent loss of renal function. However, the pathophysiological mechanisms associated with the transition from AKI to CKD under conditions of drug nephrotoxicity, diabetes mellitus or renal ischemia/reperfusion are poorly understood. Thus, the current proposal is composed of two subprojects whose objective is to point out the main mechanisms involved in the progression of kidney diseases, highlighting the podocyte lesion in the adriamycin-induced focal segmental glomerulosclerosis (FSGS) model, as well as glomerular injury, interstitial and tubular in renal ischemia/reperfusion model associated or not to diabetes. Our hypothesis is that in the adriamycin-induced FSGS model, proteinuria-associated podocyte injury is related to sustained endoplasmic reticulum stress, reduced sirtuin-1 expression, and increased claudin-1 expression, as well as increased of the apoptotic response. In the renal ischemia/reperfusion model, the pre-existence of diabetes associated with inflammatory and fibrotic processes should potentiate acute renal injury by anticipating the progression of chronic kidney disease. Experimental models: Mice of the 5 week old BALBc will be used for the induction of FSGS by adriamycin or treatment with SRT1720-sirtuin-1 agonist (CEUA-ICB / USP No. 3425170518). Mice of the 8 week old C57BL/J will be used for the induction of diabetes induction by streptozotocin and renal ischemia/reperfusion (CEUA-ICB / USP No. 12/2017). In vitro studies will be performed in primary culture from BALBc mice and podocytes cell line. In this study, the expression of sirtuin-1 and claudin-1 in human kidney biopsies with FSGS will also be evaluated. Predicted methodologies include plasma and urine metabolic parameters analysis, quantitative PCR (qPCR) to evaluate the expression of mRNA in the renal tissue, western blotting, immunofluorescence and immunohistochemistry to evaluate the expression of proteins, inflammatory and fibrotic factors, as well as analyzes of renal tissue. Statistical analysis of the results will be performed by one-way or two-way ANOVA methods and the Bonferroni post-test; p <0.05 will be considered significant in comparison to the respective control groups. The results will be presented as mean ± standard error. (AU)