Preventive role of valproic acid in the evolution of acute kidney injuries after ischemia followed by reperfusion

• Grant number: 23/13825-0
• Support Opportunities: Scholarships in Brazil - Program to Stimulate Scientific Vocations
• Start date: January 04, 2024
• End date: February 23, 2024
• 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), characterized by a decrease in filtration function within hours or days. Depending on the severity of the insult, patients with AKI may require renal replacement therapy (RRT), as current pharmacological therapy is not efficient in preventing or reversing the established condition. In Brazil, RRT incurs an annual cost of 3 billion Brazilian 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 histones being their main substrate. Deacetylated histones allow DNA to open and the process of gene expression, leading to endoplasmic reticulum stress and apoptosis activation. 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-inhibitor of histone deacetylases (HDACs). The working hypothesis is that oral administration of VPA before a renal I/R episode prevents the development of structural and functional injuries, thus avoiding progression to chronic kidney disease. Four groups of Wistar rats will be developed: (i) sham-operated without the drug; (ii) subjected to I/R; (iii) sham-operated previously treated with VPA (100 mg × kg-1 × day-1); and (iv) subjected to I/R after drug treatment. The project aims 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 project intends, by its conclusion, to determine the role of HDACs in the progression of renal disease and propose the nephroprotective mechanism of action of VPA. (AU)