From the Diabetes and Cardiovascular Center (A.R.A., J.H., R.N., J.R.S., G.J., A.W.-C.).
Department of Medicine (A.R.A., J.H., R.N., J.R.S., G.J., A.W.-C.).
Hypertension. 2019 Apr;73(4):849-858. doi: 10.1161/HYPERTENSIONAHA.118.12198.
Obesity is characterized by enhanced MR (mineralocorticoid receptor) activation, vascular stiffness, and associated cardiovascular and kidney disease. Consumption of a Western-style diet (WD), high in saturated fat and refined carbohydrates, by female mice, leads to obesity and vascular stiffening. Use of ECMR (endothelial cell-specific MR) knockout mice supports that ECMR activation is critical for development of vascular and cardiac fibrosis and stiffening. However, the role of ECMR activation in kidney inflammation and fibrosis remains unknown. We hypothesized that cell-specific deletion of ECMR would prevent WD-induced central aortic stiffness and protect the kidney from endothelial dysfunction and vascular stiffening. Four-week-old female ECMR KO and wild-type mice were fed either mouse chow or WD for 16 weeks. WD feeding increased body weight and fat mass, proteinuria, as well as vascular stiffness indices (pulse wave velocity and kidney artery stiffening) and impaired endothelial-dependent vasodilatation without blood pressure changes. The WD-induced kidney arterial stiffening was associated with attenuated eNOS (endothelial NO synthase) activation, increased oxidative stress, proinflammatory immune responses, alterations in extracellular matrix degradation pathways, and fibrosis. ECMR deletion prevented these abnormalities by improving eNOS activation and reducing macrophage proinflammatory M1 polarization, expression of TG2 (transglutaminase 2), and MMP (matrix metalloproteinase)-9. Our data support the concept that ECMR activation contributes to endothelial dysfunction, increased kidney artery fibrosis/stiffening, and impaired NOS (NO synthase) activation, processes associated with macrophage infiltration and polarization, inflammation, and oxidative stress, collectively resulting in tubulointerstitial fibrosis in females consuming a WD.
肥胖的特征是增强的 MR（盐皮质激素受体）激活、血管僵硬以及相关的心血管和肾脏疾病。雌性小鼠摄入富含饱和脂肪和精制碳水化合物的西式饮食（WD）会导致肥胖和血管僵硬。使用内皮细胞特异性 MR（ECMR）敲除小鼠支持 ECMR 激活对于血管和心脏纤维化和僵硬的发展至关重要。然而，ECMR 激活在肾脏炎症和纤维化中的作用尚不清楚。我们假设 ECMR 的细胞特异性缺失将防止 WD 诱导的主动脉僵硬，并保护肾脏免受内皮功能障碍和血管僵硬的影响。4 周龄雌性 ECMR KO 和野生型小鼠分别用小鼠饲料或 WD 喂养 16 周。WD 喂养增加了体重和脂肪量、蛋白尿以及血管僵硬指数（脉搏波速度和肾动脉僵硬），并损害了内皮依赖性血管舒张而不改变血压。WD 诱导的肾脏动脉僵硬与 eNOS（内皮型一氧化氮合酶）激活减弱、氧化应激增加、促炎免疫反应、细胞外基质降解途径改变和纤维化有关。ECMR 缺失通过改善 eNOS 激活和减少巨噬细胞促炎 M1 极化、TG2（转谷氨酰胺酶 2）和 MMP（基质金属蛋白酶）-9 的表达来预防这些异常。我们的数据支持这样的概念，即 ECMR 激活导致内皮功能障碍、增加肾脏动脉纤维化/僵硬以及 NO 合酶（NOS）激活受损，这些过程与巨噬细胞浸润和极化、炎症和氧化应激有关，共同导致女性食用 WD 时的肾小管间质纤维化。
