Modified Intestinal apoAI-particles and Lymphatics Accelerate CKD-driven CVD

心血管疾病(CVD)与肠道生物失调和慢性肾脏疾病有关， 慢性肾脏病(CKD)破坏肠道上皮完整性，扰乱碳水化合物和蛋白质代谢 刺激肠道毒素的物质。这些毒素通过器官间作用使不良反应永久化。 串扰被称为肾-肠道-心血管轴，涉及血管和神经。 我们的建议挑战了当前的研究和临床范例。我们建议任命一名新的调解人 和肾脏-肠道-心血管轴的通路。轴中的致病介体是 肠道来源的IsoLG-修饰的高密度脂蛋白。我们假设高密度脂蛋白，它在肠道中 合成的或从循环中过滤出来的，由肠道产生的IsoLG修饰。 轴上的新通路是肠系膜淋巴网络，它作为靶点和 通过增加这些血管的推进机动性并激活等LG-高密度脂蛋白效应的肇事者 淋巴管内皮细胞。IsoLG修饰的高密度脂蛋白和淋巴管一起提供了一种 肠源性促进剂持续流入促进血管功能障碍 通过肾脏-肠道-心血管轴发生动脉粥样硬化。为了检验这一假设， 我们提出了三个机械论目标。在目标1中，我们将检验CKD诱导的假设 高密度脂蛋白肠道修饰是肾-肠-心血管疾病的关键致病机制 轴心。首先，我们将定义肾脏疾病和尿毒症毒素对肠道IsoLG的影响 高密度脂蛋白的生产和修改。接下来，我们将使用肠道和肝脏特异的基因敲除 ApoAI，高密度脂蛋白的主要结构-功能蛋白，并确定CKD如何影响 肠和血浆来源的高密度脂蛋白对肠系膜淋巴高密度脂蛋白池的贡献。我们会 然后在CKD设置中确定ApoAI的特定IsoLG修改。我们还将定义 CKD和IsoLG修饰对血浆和肠系膜高密度脂蛋白-miRNA转运的影响 淋巴。在目标2中，我们将检验IsoLG修饰的高密度脂蛋白破坏结构和 肠淋巴管在慢性肾脏病中的作用。首先，我们将确定IsoLG-Modify的影响 高密度脂蛋白对慢性肾脏病患者LEC表型变化、血管完整性、收缩和淋巴管生成的影响。 然后我们将确定高密度脂蛋白-miRNA在高密度脂蛋白和淋巴管相互作用中的作用。 网络。我们将首先确定CKD中淋巴高密度脂蛋白携带的miRNA。然后，我们将确定 慢性肾功能不全患者的肠系膜淋巴管网络及其之间的联系 CKD-高密度脂蛋白与淋巴管和淋巴管内皮细胞功能障碍。在《目标3》中，我们将 验证IsoLG可以减少动脉粥样硬化中CKD驱动的加速作用的假设 清道夫，减轻肠道等LG加成脂蛋白和淋巴功能障碍。

Cardiovascular disease (CVD) has been linked to intestinal dysbiosis and chronic kidney disease, (CKD) disrupts the intestinal epithelial integrity and disturbs carbohydrate and protein metabolism that stimulate intestinal toxins. These toxins perpetuate the adverse effects through interorgan crosstalk known as the kidney-gut-cardiovascular axis that involves blood vessels and nerves. Our proposal challenges current research and clinical paradigms. We propose a new mediator and pathway in the kidney-gut-cardiovascular axis. The pathogenic mediator in the axis is intestinally-originating IsoLG-modified HDL. We hypothesize HDL, which is intestinally synthesized or filtered from the circulation, becomes modified by intestinally-generated IsoLG. The new pathway in the axis is the mesenteric lymphatic network that serves as a target and perpetrator for IsoLG-HDL effects by increasing propulsive mobility in these vessels and activating lymphatic endothelial cells. Together, the IsoLG-modified HDL and lymphatic vessels provide a sustained influx of intestinally-derived accelerants promoting vascular dysfunction and the development of atherosclerosis via the kidney-gut-cardiovascular axis. To test this hypothesis, we propose three mechanistic aims. In Aim 1, we will test the hypothesis that CKD-induced intestinal modification of HDL is a key pathogenic mechanism in the kidney-gut-cardiovascular axis. First, we will define the impact of kidney disease and uremic toxins on intestinal IsoLG production and modification of HDL. Next, we will use intestinal versus liver-specific knockouts of apoAI, the main structure-function protein of HDL, and ascertain how CKD impacts the contribution of intestinal- and plasma-derived HDL to the mesenteric lymph HDL pool. We will then determine the specific IsoLG modifications of apoAI in the CKD setting. We will also define the impact of CKD and IsoLG-modification on HDL-miRNA transport in plasma and mesenteric lymph. In Aim 2, we will test the hypothesis that IsoLG-modified HDL disrupts the structure and function of intestinal lymphatics in CKD. First, we will determine the impact of IsoLG-modified HDL on LEC phenotypic changes, vessel integrity, contractility, and lymphangiogenesis in CKD. We will then determine the role of HDL-miRNA in the interactions between HDL and the lymphatic network. We will first identify miRNA carried by lymphatic HDL in CKD. Then, we will determine the mesenteric lymphatic vascular network in humans with CKD and assess the link between CKD-HDL and dysfunction of lymphatic vessels and lymphatic endothelial cells. In Aim 3, we will test the hypothesis that CKD-driven acceleration in atherosclerosis can be reduced by IsoLG scavengers that lessen intestinal IsoLG-adducted lipoproteins and lymphatic dysfunction.