title: Mineralocorticoid receptor blockade prevents vascular remodelling in a rodent model of type 2 diabetes mellitus.
abstract: 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.
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14.049-900, Brazil.
authors.forename: Marcondes Alves B
authors.initials: MA
authors.lastname: Silva
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14.049-900, Brazil.
authors.forename: Stefany Bruno A
authors.initials: SB
authors.lastname: Cau
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14.049-900, Brazil.
authors.forename: Rheure Alves M
authors.initials: RA
authors.lastname: Lopes
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14.049-900, Brazil.
authors.forename: Carla P
authors.initials: CP
authors.lastname: Manzato
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14.049-900, Brazil.
authors.forename: Karla B
authors.initials: KB
authors.lastname: Neves
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14.049-900, Brazil.
authors.forename: Thiago
authors.initials: T
authors.lastname: Bruder-Nascimento
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14.049-900, Brazil.
authors.forename: Fabiola Leslie Antunes C
authors.initials: FL
authors.lastname: Mestriner
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G128TA, U.K.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G128TA, U.K.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G128TA, U.K.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14.049-900, Brazil rtostes@usp.br.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004996:Ethidium / Q000031:analogs & derivatives / Q000737:chemistry; D005938:Glucocorticoids / Q000378:metabolism; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000737:chemistry*; D008901:Mineralocorticoids / Q000378:metabolism; D011188:Potassium / Q000097:blood; D017382:Reactive Oxygen Species / Q000737:chemistry; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D013148:Spironolactone / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D005938:Glucocorticoids; D007328:Insulin; D000451:Mineralocorticoid Receptor Antagonists; D008901:Mineralocorticoids; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; C067883:dihydroethidium; D013148:Spironolactone; D000450:Aldosterone; D003094:Collagen; D002784:Cholesterol; D004996:Ethidium; D011188:Potassium
keywords: db/db mice; diabetes; mineralocorticoid receptor; spironolactone; vascular remodelling; vascular stiffness