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Mineralocorticoid receptor blockade prevents vascular remodelling in a rodent model of type 2 diabetes mellitus

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Silva, Marcondes Alves B. [1] ; Cau, Stefany Bruno A. [1] ; Lopes, Rheure Alves M. [1] ; Manzato, Carla P. [1] ; Neves, Karla B. [1] ; Bruder-Nascimento, Thiago [1] ; Mestriner, Fabiola Leslie Antunes C. [1] ; Montezano, Augusto C. [2] ; Cat, Aurelie Nguyen Dinh [2] ; Touyz, Rhian M. [2] ; Tostes, Rita C. [1]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, BR-14049900 Ribeirao Preto - Brazil
[2] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark - Scotland
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: Clinical Science; v. 129, n. 7, p. 533-545, OCT 1 2015.
Citações Web of Science: 16

Mineralocorticoid receptors (MRs), which are activated by mineralocorticoids and glucocorticoids, actively participate in mechanisms that affect the structure and function of blood vessels. Although experimental and clinical evidence shows that vascular damage in diabetes is associated with structural alterations in large and small arteries, the role of MR in this process needs further studies. Thus, we tested the hypothesis that MR, through redox-sensitive mechanisms, plays a role in diabetes-associated vascular remodelling. Male, 12-14-weeks-old db/db mice, a model of type 2 diabetes and their non-diabetic counterpart controls (db/+) were treated with spironolactone (MR antagonist, 50 mg/kg/day) or vehicle for 6 weeks. Spironolactone treatment did not affect blood pressure, fasting glucose levels or weight gain, but increased serum potassium and total cholesterol in both, diabetic and control mice. In addition, spironolactone significantly reduced serum insulin levels, but not aldosterone levels in diabetic mice. Insulin sensitivity, evaluated by the HOMA (homoeostatic model assessment)-index, was improved in spironolactone-treated diabetic mice. Mesenteric resistance arteries from vehicle-treated db/db mice exhibited inward hypertrophic remodelling, increased number of smooth muscle cells and increased vascular stiffness. These structural changes, determined by morphometric analysis and with a myography for pressurized arteries, were prevented by spironolactone treatment. Arteries from vehicle-treated db/db mice also exhibited augmented collagen content, determined by Picrosirius Red staining and Western blotting, increased reactive oxygen species (ROS) generation, determined by dihydroethidium (DHE) fluorescence, as well as increased expression of NAD(P)H oxidases 1 and 4 and increased activity of mitogen-activated protein kinases (MAPKs). Spironolactone treatment prevented all these changes, indicating that MR importantly contributes to diabetes-associated vascular dysfunction by inducing oxidative stress and by increasing the activity of redox-sensitive proteins. (AU)

Processo FAPESP: 10/52214-6 - Contribuição do estresse oxidativo e enzimas NADPH oxidases (NOXes) para as lesões vasculares e renais associadas ao diabetes
Beneficiário:Rita de Cassia Aleixo Tostes Passaglia
Linha de fomento: Auxílio à Pesquisa - Regular