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.
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