Modulation of Angiotensin-(1-7)/Mas axis on diabetic model: the role of stem cells on renal and cardiovascular inflammation

• Grant number: 14/23852-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): April 01, 2015
• Effective date (End): August 31, 2016
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Dulce Elena Casarini
• Grantee: Bruno Sevá Pessôa
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 10/51904-9 - Renin angiotensin and kallikrein kinin systems in hypertension, obesity, diabetes, desnutrition and sepsis: molecular, cellular and physiopathologic mechanisms, AP.TEM

Abstract

Angiotensin-(1-7) (Ang-(1-7)) is a hormone of the renin-angiotensin system (RAS) that opposes the pathophysiological effects of Angiotensin II (Ang II). Several groups have shown repeatedly that Ang-(1-7) protects the endothelium and the heart. Furthermore, the clinically applied angiotensin-converting enzyme inhibitors and Ang II type 1 receptor blockers are believed to at least partly act through increase of Ang-(1-7)/Mas receptor signaling. However, the protective mechanisms of Ang-(1-7)/Mas receptor signaling is not exactly known. Another possibility is that Ang-(1-7)/Mas signaling might have a protective role by opposing cardiac inflammation. One of the main detrimental effects of Ang II is the mediation of inflammation in cardiovascular and renal tissue through the AT1 receptor. Recently, cardiac dysfunction was associated with cardiac inflammation and remodeling in an experimental diabetic cardiomyopathy model. Moreover, Ang II-induced mice showed increased levels of inflammatory markers and cardiorenal remodeling. The receptor for Ang-(1-7) through which Ang II is antagonized and through which protective effects are mediated, the Mas receptor, is also expressed in the heart, kidney and vascular tissue. Therefore, Ang-(1-7) might have an anti-inflammatory effect in these tissues. Recently, some groups showed effects of Ang-(1-7) on inflammation that might be beneficial for cardiovascular function. Ang-(1-7) functionally antagonized Ang II-induced stimulation of monocyte adhesion and reduced pro-inflammatory responses on endothelial cells. Apart from vascular tissue, anti-inflammatory Ang-(1-7) effects are seen in a variety of other organs. The infusion of Ang-(1-7) also promotes proliferation of hematopoietic and endothelial progenitor cells and the increased levels of these cells are associated with improvement of cardiorenal function on patients with ischemic cardiac and chronic kidney diseases. The set of possible anti-inflammatory pathways of Ang-(1-7) in these studies have also been related to cardiovascular e renal systems. However, the role of Ang-(1-7) on stem cells and its effects on cardiovascular and renal inflammation has never been directly investigated. The exploration of anti-inflammatory properties of Ang-(1-7)/Mas pathway will improve our understanding of this new intervention pathway and open new possible treatments for diabetic complications. In this study we will investigate the hypothesis that increased Ang (1-7) promotes the recruitment of mesenchymal stem cells and hematopoietic reducing renal and cardiac inflammatory response in vivo model using diabetic NOD mice.