Chronic kidney disease (CKD) affects 13.4% of adults in America; and 38% in people aged 65 years or older[1]. In addition, cardiovascular disease (CVD) is the leading cause of death in CKD patients with end-stage kidney disease. CKD is associated with chronic inflammation, which contributes to the progression of CVD[2]. Furthermore, CKD alter apolipoprotein profile and elevate plasma lipid levels. It has been reported that 68.8% of CKD patients are associated with hyperlipidemia[3]. Therefore, hyperlipidemia is the critical risk factor for cardiovascular morbidity and mortality in CKD patients [4, 5]. In addition, trained immunity has been shown to play a critical role in chronic inflammatory diseases[6]. However, whether trained immunity promotes the inflammation in hyperlipidemia-CKD remains unclear. Circulating lipopolysaccharide (LPS) is significantly increased in atherosclerotic and CKD patients[7]. Clinical data indicates that circulating LPS is positively associated with the progression of CKD, and its levels even higher in patients with hemodialysis or dialysis[8]. Studies found that circulating LPS is delivered into cytosol for caspase-4/11 activation[9]. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) involving 10,061 patients found that targeting interleukin-1β (IL-1β) innate immunity pathway is significantly lowered the rate of recurrent cardiovascular events independent of lipid-level lowering[10]. Therefore, inhibiting the secretion of proinflammatory cytokine IL-1β has high potential to future development of novel therapeutics for hyperlipidemia-CKD accelerated CVD. Gasdermin D (GSDMD) is cleaved by inflammatory caspase-1 and caspase-4. N-terminal GSDMD binds to plasma membrane forming protein channel [11] and mediates the secretion of IL-1β[12, 13]. We found that caspase-1 activation was significantly decreased in caspase-4/11 deficient high-fat diet (HFD)-CKD mice, indicating that caspase-4 could regulate caspase-1 activation in HFD-CKD. Whether increased cytosolic LPS contribute to the increased vascular inflammation via caspase-4/11-GSDMD-IL-1β pathway remains unknown. In this study, we used HFD fed 5/6 nephrectomy CKD mice in vivo and cytosolic LPS stimulation in human aortic endothelial cell (HAECs) in vitro. We made the following results: 1) Inflammatory pathways are significantly increased in the aorta of HFD-CKD compared to HFD-Sham, normal diet (ND)-CKD, and ND-Sham. 2) Expression levels of endothelial cell activation markers (ICAM1 and VCAM1) are significantly increased in the aorta of HFD-CKD mice compared to HFD-Sham, ND-CKD, and ND-Sham. 3) Caspase-4 activation and N-GSDMD cleavage are significantly increased in the aorta of HFD-CKD mice compared to HFD-Sham, ND-CKD, and ND-Sham and in cytosolic LPS stimulated HAECs. 4) The increased inflammatory pathways and increased expression of adhesion molecules are decreased in the deficiency of caspase-4 in vivo and in the presence of caspase-4 inhibitor and N-terminal GSDMD cleavage inhibitor in vitro. 5) The increased mitochondrial ROS promote endothelial cell activation via caspase-4-GSDMD axis. Taken together, the caspase-4/11-GSDMD axis mediates endothelial cell activation and vascular inflammation in the aorta of HFD-CKD mice compared to controls. Furthermore, the increased endothelial cell activation and vascular inflammation are restored by caspase-4/11 deficiency in the aorta of HFD-CKD mice. These evidence indicate that inhibiting caspase-4/11-GSDMD axis could be a potential therapeutic target for inhibiting vascular inflammation associated with hyperlipidemia-CKD. / Biomedical Sciences
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/7352 |
| Date | January 2021 |
| Creators | SUN, YU, 0000-0002-0877-7186 |
| Contributors | Yang, Xiaofeng, Wang, Hong, 1956 September 19-, Park, Joon Young, Yu, Jun, Khan, Mohsin |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 136 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/7331, Theses and Dissertations |
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