Effects of valproic acid in the acute kidney injury induced by isquemia-reperfusion

• Grant number: 24/18254-3
• Support Opportunities: Scholarships in Brazil - Program to Stimulate Scientific Vocations
• Start date: February 17, 2025
• End date: April 04, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Adalberto Ramon Vieyra
• Grantee: Isadora Gonçalves Almeida
• Host Institution: Instituto de Biofísica Carlos Chagas Filho (IBCCF). Universidade Federal do Rio de Janeiro (UFRJ). Ministério da Educação (Brasil)

Abstract

The process of renal ischemia followed by reperfusion (I/R) is one of the main pathophysiological mechanisms leading to acute kidney injury (AKI), which is characterized by a reduction in filtration function within hours or days. Depending on the severity of the insult, the patient affected by AKI may require renal replacement therapy (RRT), as current pharmacological therapy is not effective in preventing the progression or reversing the established condition. In Brazil, RRT generates an annual cost of 3 billion reais, with 85% subsidized by the Unified Health System (SUS). Histone deacetylases (HDACs) are a group of enzymes that induce global changes in gene transcription and protein expression by removing acetyl groups, with histone being their main substrate. When acetylated, histones allow for the opening of DNA and the process of gene expression, which leads to endoplasmic reticulum stress and the activation of apoptosis. The nephroprotective effect of HDAC inhibitors is controversial in the literature. Valproic acid (VPA), a well-established therapy for seizures and bipolar disorder, is a pan-HDAC inhibitor. The working hypothesis is that oral administration of VPA before a renal I/R episode prevents the development of structural and functional injuries, thereby preventing the progression of chronic kidney disease. Four groups of Wistar rats will be developed: (i) sham-operated rats that will not receive the drug; (ii) subjected to I/R; (iii) sham-operated rats pre-treated with VPA (100 mg × kg-1 × day-1); and (iv) subjected to I/R after drug treatment. The project's objective is to investigate the potential effects of VPA administration in preventing renal structural and functional changes after an acute I/R episode in rats up to 72 hours. Systolic blood pressure (SBP) will also be monitored to demonstrate the impact of AKI on SBP and the effect of VPA treatment. The aim is to determine the role of HDACs in the progression of kidney disease and propose the nephroprotective mechanism of action of VPA by the end of the project.