Identification of a novel gene to promote atherosclerosis development by regulating fatty acid binding protein secreted from dysfunctional kidney

鉴定一种通过调节功能失调的肾脏分泌的脂肪酸结合蛋白来促进动脉粥样硬化发展的新基因

• 批准号: 21590957
• 负责人: YAMADA Hiroyuki
• 金额: $ 3万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590957/
• 关键词: 血管病態学; 動脈硬化; 慢性腎臓病; 脂肪組織; レニン・アンジオテンシン系; 脂肪酸代謝; 脂肪酸結合蛋白; 血管病態学; 動脈硬化; 慢性腎臓病; 脂肪組織; レニン・アンジオテンシン系; 脂肪酸代謝; 脂肪酸結合蛋白

In this study, we demonstrated for the first time that exaggerated atherosclerosis development elicited by uninephrectomy was closely associated with PAT-specific increases in AGT mRNA expression and Ang II secretion without enhanced recruitment of monocytes/macrophages. HOMA-IR index and plasma insulin concentrations after glucose loading were markedly elevated in uninephrectomized apoE^<-/-> mice, and insulin stimulation of isolated PAT mature adipocytes significantly increased AGT mRNA expression in a depot-specific manner, suggesting that insulin resistance-associated hyperinsulinemia most likely contributed to the PAT-specific activation of RAS. In contrast, expression of adhesion molecules in the vasculature and the number of circulating inflammatory monocytes, which played a crucial role in the early stage of atherosclerosis development, were not altered by uninephrectomy. Moreover, accelerated atherosclerosis development caused by uninephrectomy was completely inhibited in apoE^<-/->/AT1aR^<-/-> mice or by treatment with angiotensin II type 1 receptor blocker(olmesartan), further supporting the notion that PAT-specific activation of RAS is substantially involved in the CKD-associated atherogenesis and could be a novel therapeutic target for the prevention of CKD-associated cardiovascular disease.

在这项研究中，我们首次证明了夸张的动脉粥样硬化发育是由单晶切除术引起的，这与AGT mRNA表达的PAT特异性增加和ANG II分泌的分泌密切相关，而无需增强单核细胞/巨噬细胞的募集。葡萄糖负荷后的HOMA-IR指数和血浆胰岛素浓度在非肾脏切除型APOE^< - / - >小鼠中显着升高，以及分离的PAT成熟成熟脂肪细胞的胰岛素刺激显着增加了depot特异性的AGT mRNA表达，这表明胰岛素抵抗性超拟合量可能贡献了胰岛素抗性的高度促进量的贡献。相比之下，脉管系统中粘附分子的表达和循环炎性单核细胞的数量在动脉粥样硬化发育的早期发挥了至关重要的作用，并没有通过单态切除术改变。此外，在APOE^< - / - >/AT1AR^< - / - >小鼠或用Angiotensin II类型1型受体阻滞剂（Olmesartan）治疗中，完全抑制了由单晶切除术引起的加速动脉粥样硬化发展，完全抑制了RAS的概念，并以ckd-Assection ckd-aSentive ckd-and senter consection ckd- CKD相关的心血管疾病。