Abstract
Cardiovascular disease (CVD) is the leading cause of mortality in diabetes mellitus (DM). Immunomodulatory dysfunction is a primary feature of DM, and the emergence of chronic kidney disease (CKD) in DM abruptly increases CVD mortality compared with DM alone. Endothelial injury and the accumulation of uremic toxins in the blood of DM/CKD patients are known mechanisms for the pathogenesis of CVD. However, the molecular factors that cause this disproportional increase in CVD in the DM/CKD population are still unknown. Since long non-protein-coding RNAs (lncRNAs) play an important role in regulating multiple cellular functions, we used human endothelial cells treated with high glucose to mimic DM and with the uremic toxin indoxyl sulfate (IS) to mimic the endothelial injury associated with CKD. Differentially expressed lncRNAs in these conditions were analyzed by RNA sequencing. We discovered that lnc-SLC15A1-1 expression was significantly increased upon IS treatment in comparison with high glucose alone, and then cascaded the signal of chemokines CXCL10 and CXCL8 via sponging miR-27b, miR-297, and miR-150b. This novel pathway might be responsible for the endothelial inflammation implicated in augmenting CVD in DM/CKD and could be a therapeutic target with future clinical applications.
Highlights
Diabetes mellitus (DM) is a metabolic disease characterized by dysregulation of glucose
We discovered a novel pathway by which lnc-SLC15A1-1 upregulates the chemokines CXCL10 and CXCL8 via its function as a miRNA sponge in human umbilical vein endothelium cells (HUVECs) subjected to endothelial injury
Given that endothelial cells incubated with uremic serum significantly increased the levels of inflammatory biomarkers of IL-6, IL-8, MCP-1, and PAI-1 [46], we aimed to evaluate the impact of indoxyl sulfate (IS) on the high glucose endothelial cells to clarify the injury mechanism of diabetes mellitus (DM)/chronic kidney disease (CKD) patients’ endothelium
Summary
Diabetes mellitus (DM) is a metabolic disease characterized by dysregulation of glucose. For CKD patients, one of the most important triggers of CVD is endothelium dysfunction. This happens via the accumulation of various uremic toxins (UTs) that have a deleterious impact on endothelial cells [12]. Among these UTs, the protein-bound solute, indoxyl sulfate (IS), has been shown to be associated with high cardiovascular risk and mortality [13]. Many studies have reported that IS is a nephrovascular toxin that increases the expression of inflammation-associated genes [14] and thereby contributes to high cardiovascular risk and mortality [15,16]. Systemic inflammatory activity is an established pathogenic mechanism of CVD in the context of DM and/or CKD, the specific molecular factors contributing to the augmented incidence of CVD events in DKD remains unknown
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