Hyperlipidemia and chronic kidney disease (CKD) are well-established risk factors for cardiovascular disease and act synergistically to promote vascular inflammation and disease progression. However, Show more
Hyperlipidemia and chronic kidney disease (CKD) are well-established risk factors for cardiovascular disease and act synergistically to promote vascular inflammation and disease progression. However, the mechanisms underlying this synergetic effect remain largely unknown. Using a mouse model combining hyperlipidemia (via high-fat diet feeding, HFD) with 5/6 nephrectomy-induced CKD, we made the following significant findings: 1) HFD + CKD upregulated 1179 genes in mouse aortas and induced prominent reactive oxygen species (ROS), far more than either HFD or CKD alone. 2) HFD + CKD upregulated 86 CRISPRi-identified mitochondrial ROS regulators, 36 CRISPRi-identified cellular ROS regulators, and 19 GSEA-collected ROS regulators. These changes were associated with the upregulations of 48 cytokines, 7 highest toxicity uremic toxin receptors-including CD1D, FCGRT, AHR, IL6RA AGER, NR1H3 and NPY5R-in aortas. 3) These uremic toxin receptors emerged as novel promoters of inflammation and trained immunity. Deficiencies in CD1D, AHR, AGER, and the trained immunity promoter SET7 each downregulated up to 5.5 % of the genes upregulated by HFD + CKD. Conversely, activation of NR1H3 using an agonist upregulated up to 12.2 % of these genes. 4) The expression of 46 cytokine genes was strongly associated with NR1H3 upregulation. 5) The NR1H3 agonist also induced the expression of 28 ROS regulators, including YBX2, a novel anti-ROS transcription factor and RNA-binding protein, suggesting a potential negative feedback mechanism. YBX2 deficiency increased the cellular ROS level, while YBX2 overexpression suppressed 27 proinflammatory genes induced by HFD + CKD. Our findings provide novel insights into the role of the NR1H3-YBX2 axis in regulating inflammation accelerated by hyperlipidemia and CKD. Show less