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Contribution of oxidative stress and NADPH oxidase (NOXes) diabetes-associated vascular injury: study in knockout mice

Grant number: 11/22035-5
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): July 15, 2012
Effective date (End): July 14, 2013
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Principal researcher:Rita de Cassia Aleixo Tostes Passaglia
Grantee:Thiago Bruder Do Nascimento
Supervisor abroad: Rhian M. Touyz
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: University of Ottawa (uOttawa), Canada  
Associated to the scholarship:11/01785-6 - Contribution of oxidative stress and NOXes to diabetes-associated vascular injury, BP.DR

Abstract

Diabetes Mellitus stands out as one of the most important non-transmissible chronic diseases worldwide. Epidemiological, clinical and experimental data indicate a causal association between hyperglycemia and diabetic complications. Exact mechanisms for this remain elusive but hyperglycaemia-induced oxidative stress appears to play an important role in the increased risk of diabetic complications, including diabetic nephropathy, cardiovascular disease and retinopathy. This proposal aims to determine the role of NOX1/NOX4-derived ROS in the pathogenesis of diabetic vasculopathy due to type 2 diabetes and, therefore, to elucidate redox-sensitive molecular mechanisms of the disease. Our hypothesis is that diabetes is associated with tissue-specific activation of different NOX isoforms: hyperactivation of vascular NOX1 causing vascular injury and upregulation of renal NOX4 leading to nephropathy. This NOX isoform effect is related to differential expression of p47phox and its isoform NOXO1. We will focus on two specific aims: 1) db/db mice (C57BLKS/JLepr), considered a diabetic nephropathy model, will be crossed with knockout mice NOX1 (NOX1-/-), NOX 4 (NOX4-/-) e p47phox-/-, and the vascular alterations will be characterized. To elucidate the role of NOXes1/4 and p47phox in diabetes-associated renal and vascular complications, db/db (C57BLKS/JLepr) mice will be crossed with NOX1-/-, NOX4-/- and p47phox-/- mice. This set of experiments will be performed at the University of Ottawa. 2) mesenteric artery will be isolated of diabetic and control mice. Vascular cultured cells (smooth muscle) from these animals will be used to determine the molecular pathways that are involved on ROS generation mediated by NOXes 1 and 4, as well as, the pathway NOX-dependent for proliferation and inflammation. (AU)

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Scientific publications (4)
(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)
BRUDER-NASCIMENTO, T.; CHINNASAMY, P.; RIASCOS-BERNAL, D. F.; CAU, S. B.; CALLERA, G. E.; TOUYZ, R. M.; TOSTES, R. C.; SIBINGA, N. E. S.. Angiotensin II induces Fat1 expression/activation and vascular smooth muscle cell migration via Nox1-dependent reactive oxygen species generation. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, v. 66, p. 18-26, . (11/22035-5, 11/01785-6)
BRUDER-NASCIMENTO, THIAGO; CALLERA, GLAUCIA; MONTEZANO, AUGUSTO CESAR; ANTUNES, TAYZE T.; HE, YING; CAT, AURELIE NGUYEN DINH; FERREIRA, NATHANNE S.; BARRETO, PEDRO A.; OLIVON, VANIA C.; TOSTES, RITA C.; et al. Renoprotective Effects of Atorvastatin in Diabetic Mice: Downregulation of RhoA and Upregulation of Akt/GSK3. PLoS One, v. 11, n. 9, . (11/22035-5, 11/01785-6)
BRUDER-NASCIMENTO, THIAGO; CALLERA, GLAUCIA E.; MONTEZANO, AUGUSTO C.; HE, YING; ANTUNES, TAYZE T.; CAT, AURELIE NGUYEN DINH; TOSTES, RITA C.; TOUYZ, RHIAN M.. Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: role of Rac1/2-sensitive Nox-dependent pathways. Clinical Science, v. 128, n. 7, p. 411-423, . (11/22035-5, 11/01785-6, 10/52214-6)
BRUDER-NASCIMENTO, THIAGO; CALLERA, GLAUCIA E.; MONTEZANO, AUGUSTO C.; DE CHANTEMELE, ERIC J. BELIN; TOSTES, RITA C.; TOUYZ, RHIAN M.. Atorvastatin inhibits pro-inflammatory actions of aldosterone in vascular smooth muscle cells by reducing oxidative stress. Life Sciences, v. 221, p. 29-34, . (10/52214-6, 11/22035-5, 11/01785-6)

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