Alternative pathways for angiotensin II production as an important determinant of kidney damage in endotoxemia

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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 ; Casarini, Dulce Elena

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY; v. 311, n. 3, p. F496-F504, SEP 1 2016.
• Web of Science Citations: 7

Abstract

Sepsis is an uncontrolled systemic inflammatory response against an infection and a major public health issue worldwide. This condition affects several organs, and, when caused by Gram-negative bacteria, kidneys are particularly damaged. Due to the importance of renin-angiotensin system (RAS) in regulating renal function, in the present study, we aimed to investigate the effects of endotoxemia over the renal RAS. Wistar rats were injected with Escherichia coli lipopolysaccharide (LPS) (4 mg/kg), mimicking the endotoxemia induced by Gram-negative bacteria. Three days after treatment, body mass, blood pressure, and plasma nitric oxide (NO) were reduced, indicating that endotoxemia triggered cardiovascular and metabolic consequences and that hypotension was maintained by NO-independent mechanisms. Regarding the effects in renal tissue, inducible NO synthase (iNOS) was diminished, but no changes in the renal level of NO were detected. RAS was also highly affected by endotoxemia, since renin, angiotensin-converting enzyme (ACE), and ACE2 activities were altered in renal tissue. Although these enzymes were modulated, only angiotensin (ANG) II was augmented in kidneys; ANG I and ANG 1-7 levels were not influenced by LPS. Cathepsin G and chymase activities were increased in the endotoxemia group, suggesting alternative pathways for ANG II formation. Taken together, our data suggest the activation of noncanonical pathways for ANG II production and the presence of renal vasoconstriction and tissue damage in our animal model. In summary, the systemic administration of LPS affects renal RAS, what may contribute for several deleterious effects of endotoxemia over kidneys. (AU)

• FAPESP's process: 10/51904-9 - Renin angiotensin and kallikrein kinin systems in hypertension, obesity, diabetes, desnutrition and sepsis: molecular, cellular and physiopathologic mechanisms
• Grantee: Dulce Elena Casarini
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/04940-2 - Angiotensin Converting Enzyme (ACE2) pathophysiological role in a sepsis-induced animal model
• Grantee: Rodolfo Mattar Rosa
• Support Opportunities: Scholarships in Brazil - Master