Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet.
Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet.
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DOI：
10.1111/j.1538-7836.2010.03976.x
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Takahashi N
中科院分区：
文献类型：
--
作者：
Li F;Wang CH;Wang JG;Thai T;Boysen G;Xu L;Turner AL;Wolberg AS;Mackman N;Maeda N;Takahashi N
人类eNOS （NOS3）多态性降低其表达与晚期糖尿病肾病（DN）有关，缺乏eNOS会加速糖尿病小鼠的DN。糖尿病与纤维蛋白沉积有关。一氧化氮和脂肪酸的缺乏刺激NF-kB通路，从而增加组织因子（TF）。为了验证高脂肪饮食对糖尿病eNOS-/-小鼠DN严重程度的影响。用链脲佐菌素诱导eNOS-/-型和野生型小鼠患糖尿病。其中一半被安排在高脂肪饮食中。血糖水平不受饮食或eNOS基因型的影响。糖尿病小鼠缺乏eNOS会增加尿白蛋白排泄、肾小球硬化、间质纤维化和肾小球基底膜厚度。HF本身不影响野生型小鼠DN，但显著增强eNOS-/-小鼠DN。超过一半的糖尿病eNOS-/-小鼠在HF中过早死亡，伴有血栓并发症的迹象。糖尿病肾脏含有纤维蛋白和TF，其水平因eNOS的缺乏和HF的增加而增加。HF饮食增加了肾脏炎症基因的表达。在糖尿病小鼠发生DN之前，TF增加，给糖尿病小鼠注射抗小鼠TF抗体，可以降低炎症基因的表达。总之，这些数据表明TF与eNOS-/-小鼠DN恶化之间存在因果关系。HF饮食通过TF增强炎症反应，使病情显著恶化。
Human eNOS (NOS3) polymorphisms that lower its expression are associated with advanced diabetic nephropathy (DN), and the lack of eNOS accelerates DN in diabetic mice. Diabetes is associated with fibrin deposition. Lack of nitric oxide and fatty acids stimulate the NF-kB pathway, which increases tissue factor (TF). To test the hypothesis that TF contributes to the severity of DN in the diabetic eNOS-/- mice fed a high fat (HF) diet. We made eNOS-/- and wild type mice diabetic with streptozotocin. Half of them were placed on a high fat (HF) diet. Blood glucose levels were not affected by either the diet or eNOS genotype. Lack of eNOS in the diabetic mice increased urinary albumin excretion, glomerulosclerosis, interstitial fibrosis, and glomerular basement membrane thickness. HF by itself did not affect DN in the wild type mice, but significantly enhanced DN in eNOS-/- mice. More than half of diabetic eNOS-/- mice on HF died prematurely with signs of thrombotic complications. Diabetic kidneys contained fibrin and TF, and their levels were increased by the lack of eNOS and by HF in an additive fashion. The HF diet increased the kidney expression of inflammatory genes. The increase in TF preceded DN, and administration of an anti-mouse TF antibody to diabetic mice reduced the expression of inflammatory genes. Together, these data indicate a causal link between TF and the exacerbation of DN in eNOS-/- mice. The condition is significantly worsened by enhanced inflammatory responses to a HF diet via TF.
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