Angiotensin Converting Enzyme (ACE2) pathophysiological role in a sepsis-induced animal model

• Grant number: 11/04940-2
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): August 01, 2011
• Effective date (End): June 30, 2013
• Field of knowledge: Biological Sciences - Biochemistry - Enzymology
• Principal Investigator: Dulce Elena Casarini
• Grantee: Rodolfo Mattar Rosa
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated scholarship(s): 12/13710-3 - Internship propose to learn and transfer cardiomyocyte and cardiac fibroblast primary culture techniques, BE.EP.MS

Abstract

Sepsis is a major public health issue worldwide which causes around 215,000 deaths per year, and the costs of treatment may reach 17 billion dollars. This disease is defined as an uncontrolled systemic inflammatory response against an infection, and one of the major organs damaged by sepsis is the kidney, especially when the infection occurs by Gram-negative bacteria. Given the cardiovascular and renal changes provoked by sepsis, the aim of the present study was to investigate the modulation of some RAS components in the kidney of animals injected with E. coli lipopolysaccharide (LPS), a model of acute renal failure due to sepsis.Firstly, Wistar rats were injected intraperitoneally with LPS 4 mg/kg and were euthanized 3 days after treatment. Endotoxemic rats showed reduction in both body weight and blood pressure. The levels of plasmatic proinflammatory cytokines were not altered by LPS administration three days after treatment. However, the values of plasmatic NO and renal iNOS were decreased by endotoxemia. These data indicate that, in our animal model, three days after toxin injection, NO is no longer the main responsible for the hypotension and other factors may be more important for the maintenance of vasodilatation.The glomerular filtration rate did not change, which was evidenced by the maintenance in the creatinine clearance among the groups. However, renal vasoconstriction seems to be settled by LPS treatment, since high levels of Ang II were found in the kidney from endotoxemic rats. Moreover, this peptide can also be associated with the progression of the inflammatory response and it may be a possible cause of tissue damage. ACE, the main producer of renal Ang II, presented increased expression but decreased activity in the kidney, which indicates that alternative pathways of Ang II production are activated. Furthermore, renin also showed reduced activity in the endotoxic kidney, indicating an attempt in controlling RAS activity.In summary, prolonged treatment with LPS appears to activate compensatory pathways as targeting an attempt to return to homeostasis and to reduce the damage triggered by exdotoxemia. (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)

ROSA, RODOLFO MATTAR; COLUCCI, JULIANA ALMADA; YOKOTA, RODRIGO; MOREIRA, ROSELI PERES; ARAGAO, DANIELLE SANCHES; RIBEIRO, AMANDA APARECIDA; ARITA, DANIELLE YURI; MIZUNO WATANABE, INGRID KAZUE; PALOMINO, ZAIRA; CUNHA, TATIANA SOUSA; et al. Alternative pathways for angiotensin II production as an important determinant of kidney damage in endotoxemia. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 311, n. 3, p. F496-F504, SEP 1 2016. (10/51904-9, 11/04940-2)