Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8
Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8
复制标题
DOI：
10.1186/s13293-017-0141-y
复制
发表时间：
2017-05-30
影响因子：
7.9
通讯作者：
Menendez-Castro, Carlos
中科院分区：
文献类型：
--
作者：
Marek, Ines;Canu, Maurizio;Menendez-Castro, Carlos
背景：载脂蛋白E基因缺陷(APOE(-/-))小鼠随着年龄的增长发生进行性动脉粥样硬化病变，但在没有额外挑战的情况下没有严重的肾脏病理。我们最近描述了间充质整合素链Itga8(Itga8(-/-))缺陷的APOE(-/-)小鼠加速的动脉粥样硬化和显著的肾脏损伤。在这里，我们使用APOE(-/-)，Itga8(-/-)小鼠模型来研究动脉粥样硬化和伴随的肾损伤发生中的性别差异。在这个模型中，我们假设衰老的雌性小鼠可以免受血管和肾脏损伤。方法：APOE(-/-)小鼠与Itga8(-/-)小鼠回交。小鼠被保持正常饮食。在12月龄时，对雄性和雌性APOE(-/-)、Itga8(+/+)和APOE(-/-)Itga8(-/-)小鼠的主动脉和肾脏进行了观察。用苏丹IV(脂类沉积)或von Kossa(钙化)对主动脉表面标本进行染色。在肾脏组织中进行IV型胶原、CD3、F4/80和增殖细胞核抗原的免疫组织化学染色，以及IL6、Vegfa、Col1a1(I型胶原)、Ssp1(分泌型磷蛋白1，同义词骨桥蛋白)以及ER应激标志物的实时定量PCR分析。结果：与雄性小鼠相比，APOE(-/-)Itga8(+/+)雌性小鼠体重更低，血清胆固醇水平相同，甘油三酯水平更低。然而，雌性小鼠比雄性小鼠有更多的主动脉脂沉积和更多的主动脉钙化。伴有Itga8缺陷的雄性APOE(-/-)小鼠出现血清尿素升高、肾小球硬化、肾脏免疫细胞浸润和肾小球细胞增殖减少。在同一基因型的女性中，这些肾脏改变较不明显，并伴有IL-6和I型胶原的低表达，而骨桥蛋白的表达较高，ER应激指标没有差异。结论：在这种动脉粥样硬化模型中，女性是发生更严重动脉粥样硬化病变的危险因素，尽管男性的血脂水平较高。相比之下，雌性小鼠受到保护，不会受到肾脏损害，而肾脏损害伴随着炎症和基质沉积的减轻。因此，性别对血管和肾脏损伤的影响是不同的。
Background: Apoe-deficient (Apoe(-/-)) mice develop progressive atherosclerotic lesions with age but no severe renal pathology in the absence of additional challenges. We recently described accelerated atherosclerosis as well as marked renal injury in Apoe(-/-) mice deficient in the mesenchymal integrin chain Itga8 (Itga8(-/-)). Here, we used this Apoe(-/-), Itga8(-/-) mouse model to investigate the sex differences in the development of atherosclerosis and concomitant renal injury. We hypothesized that aging female mice are protected from vascular and renal damage in this mouse model.Methods: Apoe(-/-) mice were backcrossed with Itga8(-/-) mice. Mice were kept on a normal diet. At the age of 12 months, the aortae and kidneys of male and female Apoe(-/-),Itga8(+/+) mice or Apoe(-/-) Itga8(-/-) mice were studied. En face preparations of the aorta were stained with Sudan IV (lipid deposition) or von Kossa (calcification). In kidney tissue, immunostaining for collagen IV, CD3, F4/80, and PCNA and real-time PCR analyses for Il6, Vegfa, Col1a1 (collagen I), and Ssp1 (secreted phosphoprotein 1, synonym osteopontin) as well as ER stress markers were performed.Results: When compared to male mice, Apoe(-/-) Itga8(+/+) female mice had a lower body weight, equal serum cholesterol levels, and lower triglyceride levels. However, female mice had increased aortic lipid deposition and more aortic calcifications than males. Male Apoe(-/-) mice with the additional deficiency of Itga8 developed increased serum urea, glomerulosclerosis, renal immune cell infiltration, and reduced glomerular cell proliferation. In females of the same genotype, these renal changes were less pronounced and were accompanied by lower expression of interleukin-6 and collagen I, while osteopontin expression was higher and markers of ER stress were not different.Conclusions: In this model of atherosclerosis, the female sex is a risk factor to develop more severe atherosclerotic lesions, even though serum fat levels are higher in males. In contrast, female mice are protected from renal damage, which is accompanied by attenuated inflammation and matrix deposition. Thus, sex affects vascular and renal injury in a differential manner.