Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14.049-900, Brazil.
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G128TA, U.K.
Clin Sci (Lond). 2015 Oct;129(7):533-45. doi: 10.1042/CS20140758. Epub 2015 May 13.
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.
醛固酮受体 (MR) 可被醛固酮和糖皮质激素激活，积极参与影响血管结构和功能的机制。尽管实验和临床证据表明，糖尿病中的血管损伤与大、小动脉的结构改变有关，但 MR 在这一过程中的作用仍需要进一步研究。因此，我们检验了一个假说，即 MR 通过氧化还原敏感机制在糖尿病相关的血管重塑中发挥作用。我们使用 12-14 周龄的雄性 db/db 小鼠（2 型糖尿病模型）及其非糖尿病对照（db/+）作为研究对象，用螺内酯（MR 拮抗剂，50mg/kg/天）或载体处理 6 周。螺内酯治疗并未影响血压、空腹血糖水平或体重增加，但增加了两种小鼠的血清钾和总胆固醇。此外，螺内酯显著降低了糖尿病小鼠的血清胰岛素水平，但对醛固酮水平没有影响。用 HOMA（稳态模型评估）指数评估的胰岛素敏感性在螺内酯治疗的糖尿病小鼠中得到改善。用载体处理的 db/db 小鼠肠系膜阻力血管表现出内向性肥厚重塑，平滑肌细胞数量增加，血管僵硬度增加。这些结构变化通过形态计量分析和加压动脉的肌动描记术确定，螺内酯治疗可预防这些变化。用载体处理的 db/db 小鼠的血管也表现出胶原含量增加，用苦味酸红染色和 Western blot 确定；活性氧（ROS）生成增加，用二氢乙锭（DHE）荧光确定；NAD(P)H 氧化酶 1 和 4 的表达增加以及丝裂原激活蛋白激酶（MAPK）的活性增加。螺内酯治疗可预防所有这些变化，表明 MR 通过诱导氧化应激和增加氧化还原敏感蛋白的活性，对糖尿病相关的血管功能障碍有重要贡献。
