Activation of endothelial NAD(P)H oxidase accelerates early glomerular injury in diabetic mice.
Activation of endothelial NAD(P)H oxidase accelerates early glomerular injury in diabetic mice.
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DOI：
10.1038/labinvest.2015.128
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Kashihara N
中科院分区：
文献类型：
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作者：
Nagasu H;Satoh M;Kiyokage E;Kidokoro K;Toida K;Channon KM;Kanwar YS;Sasaki T;Kashihara N
活性氧（ROS）的产生增加是糖尿病血管和肾脏并发症的常见致病机制。内皮细胞NAD（P）H氧化酶是血管活性氧的主要来源，在内皮功能障碍中起重要作用。我们假设内皮细胞NAD（P）H氧化酶的激活启动和阻止糖尿病肾病的进展，特别是在蛋白尿的发展中。我们使用了内皮靶向过表达NAD（P）H氧化酶催化亚基Nox 2（NOX 2 TG）的转基因小鼠。将N 0X 2 TG小鼠与发展进行性高血糖症的秋田胰岛素依赖性糖尿病（秋田）小鼠杂交。我们比较了秋田小鼠和NOX 2 TG-秋田小鼠糖尿病肾病的进展。NOX 2 TG-秋田小鼠和秋田小鼠分别在6周龄和10周龄时出现显著高于基线的白蛋白尿。与秋田小鼠相比，NOX 2 TG-秋田小鼠表现出较高水平的NAD（P）H氧化酶活性，肾小球内皮细胞紊乱，肾小球糖萼表达减弱。此外，与秋田小鼠相反，NOX 2 TG-秋田小鼠具有许多内皮微粒（滤过泡），如通过扫描电子显微镜检测到的，并且肾小球渗透性增加。此外，NOX 2 TG-Akita小鼠在表达α-平滑肌肌动蛋白的肾小球系膜细胞和表达增加的结蛋白水平的足细胞中表现出明显的表型变化，而肾小球产生增加的ROS水平。总之，高血糖时内皮细胞NAD（P）H氧化酶的激活引发并加重了以蛋白尿为特征的糖尿病肾病。此外，在内皮细胞中产生的ROS通过改变系膜细胞的表型和损害足细胞的完整性而使肾小球功能障碍复杂化。
Increased generation of reactive oxygen species (ROS) is a common denominative pathogenic mechanism underlying vascular and renal complications in diabetes mellitus. Endothelial NAD(P)H oxidase is a major source of vascular ROS, and it has an important role in endothelial dysfunction. We hypothesized that activation of endothelial NAD(P)H oxidase initiates and worsens the progression of diabetic nephropathy, particularly in the development of albuminuria. We used transgenic mice with endothelial-targeted overexpression of the catalytic subunit of NAD(P)H oxidase, Nox2 (NOX2TG). NOX2TG mice were crossed with Akita insulin-dependent diabetic (Akita) mice that develop progressive hyperglycemia. We compared the progression of diabetic nephropathy in Akita versus NOX2TG-Akita mice. NOX2TG-Akita mice and Akita mice developed significant albuminuria above the baseline at 6 and 10 weeks of age, respectively. Compared with Akita mice, NOX2TG-Akita mice exhibited higher levels of NAD(P)H oxidase activity in glomeruli, developed glomerular endothelial perturbations, and attenuated expression of glomerular glycocalyx. Moreover, in contrast to Akita mice, the NOX2TG-Akita mice had numerous endothelial microparticles (blebs), as detected by scanning electron microscopy, and increased glomerular permeability. Furthermore, NOX2TG-Akita mice exhibited distinct phenotypic changes in glomerular mesangial cells expressing α-smooth muscle actin, and in podocytes expressing increased levels of desmin, whereas the glomeruli generated increased levels of ROS. In conclusion, activation of endothelial NAD(P)H oxidase in the presence of hyperglycemia initiated and exacerbated diabetic nephropathy characterized by the development of albuminuria. Moreover, ROS generated in the endothelium compounded glomerular dysfunctions by altering the phenotypes of mesangial cells and compromising the integrity of the podocytes.