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Evaluation of intracellular cardiac renin-angiotensin system induced by high salt consumption

Grant number: 13/08418-4
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): September 01, 2013
Effective date (End): October 31, 2017
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Joel Claudio Heimann
Grantee:Ellen Priscila Brito Dopona
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The renin angiotensin system is classically known for his systemic vasoconstriction 1. Beyond systemic action, all components required for the synthesis and action of angiotensin II are found in various organs, including the heart 2, 3. The increase of angiotensin II in the heart has been described as a potent stimulus for the development of cardiovascular diseases. Many mechanisms are involved in the increase of this peptide in the heart. A study in our laboratory observed development of blood pressure independent cardiac hypertrophy and fibrosis induced by dietary salt overload. In this study it was observed higher angiotensin II content in all groups fed high salt diet. In addition, left ventricular AT1 receptor gene and protein expression and AT2 gene expression were observed in the left ventricular myocardium. Angiotensin II acts via two main receptors 4. The AT1 receptor is involved in pathological cardiac response triggered by angiotensin II, increasing cytokines and growth factors that are related to hypertrophic and fibrotic response and with increased free radical oxygen species in the heart5, 6. Interestingly, the AT2 receptor has opposing response, thereby triggering anti-proliferative, anti-hypertrophic, vasodilation, antioxidant and anti-fibrotic effects 7, 8. This receptor is highly expressed in the fetal period, however in pathological conditions it is re-expressed and contributes to attenuate the effects of angiotensin II in the heart 8. Angiotensin II receptors were detected in mitochondrial inner membrane. Recent studies have demonstrated that angiotensin II seems to be involved with the regulation of nitric oxide generation and mitochondrial function 9, 10. Aiming to better understand the role of AT2 receptor in models of salt overload on cardiac hypertrophy and fibrosis and oxidative stress and to evaluate mitochondrial angiotensin II receptors, male Wistar rats will be fed normal salt diet (NaCl = 1,27%, n=16) or high sal diet (NaCl = 8%; n=48) from weaning up to 18 weeks of age. The high salt group will be divided into two groups to receive treatment. Starting at 7 weeks of age a group will be treated with N-acetilcistein (n = 16) which has antioxidant effect and another group will be treated with compound 21 (1mg/kg per day 11 , total amount= 733 mg, n = 16), an AT2 receptor agonist. Weight, blood pressure, food intake, water intake, urine volume, plasma and urinary sodium and potassium, cardiomyocyte transverse diameter, percentage of cardiac fibrosis, conformational status of AT1 and AT2 receptors, gene and protein expression of components of the renin angiotensin system, assessment of cardiac tissue oxidative stress. Mitochondria AT1 and AT2 receptors will be analyzed by electron microscopy using gold particles conjugated with AT1 and AT2 antibodies. (AU)

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