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

在这项研究中，我们第一次证明了单侧肾切除术引起的动脉粥样硬化发展与PAT特异性AGT mRNA表达和Ang II分泌增加密切相关，而单核细胞/巨噬细胞的募集没有增强。单肾切除apoE^<-/->小鼠在葡萄糖负荷后HOMA-IR指数和血浆胰岛素浓度显著升高，胰岛素刺激分离的PAT成熟脂肪细胞以贮库特异性方式显著增加AGT mRNA表达，这表明胰岛素抵抗相关的高胰岛素血症最可能导致RAS的PAT特异性激活。与此相反，表达的粘附分子在血管和循环炎症单核细胞的数量，这在动脉粥样硬化发展的早期阶段发挥了至关重要的作用，没有改变单肾切除术。此外，在apoE^<-/->/AT 1aR ^<-/->小鼠中或通过血管紧张素II 1型受体阻断剂（奥美沙坦）治疗完全抑制了单侧肾切除术引起的动脉粥样硬化加速发展，进一步支持了RAS的PAT特异性激活实质上参与CKD相关动脉粥样硬化形成的观点，并可能成为预防CKD相关心血管疾病的新治疗靶点。

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.