Indoxyl Sulfate Elevated Lnc-SLC15A1-1 Upregulating CXCL10/CXCL8 Expression in High-Glucose Endothelial Cells by Sponging MicroRNAs

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.

LINC00926 is involved in hypoxia-induced vascular endothelial cell dysfunction <em>via</em> miR-3194-5p regulating JAK1/STAT3 signaling pathway

“…19 Lin et al 20 reported that lncRNA THRIL relieved myocardial injury via miRNA-424/TXNIP/p53 aixs in CHD mice. Huang et al 21 confirmed that lnc-SLC15A1-1 upregulated CXCL10 and CXCL8 levels by sponging miRNA in HUVECs. In our study, both hypoxia treatment and overexpressed LINC00926 downregulated the level of miR-3194-5p, upregulated the levels of JAK1 and p-STAT3.…”

Causal relationships between blood metabolites and diabetic retinopathy: a two-sample Mendelian randomization study

“…Meanwhile, multiple metabolomics analyses of plasma/serum from DR patients have also identified TRP and KYN as potential biomarkers of DR ( 10 , 37 ). Indoxyl sulfate, a uremic toxin produced by bacterial decomposition of intestinal amino acids, especially TRP, has been reported to be involved in the metabolic disorder of DN ( 38 ). Our research suggested that 3-indoxyl sulfate may serve as a potential risk factor for DR, although further confirmation is required through experiments.…”

Fecal Microbiota Transplantation in Reducing Uremic Toxins Accumulation in Kidney Disease: Current Understanding and Future Perspectives

“…The effect of several uremic toxins on vascular dysfunction may also be due to their ability to modulate the downstream expression of many intracellular miRNAs in endothelial cells [ 73 , 74 ]. Altogether, this evidence highlights that uremic toxins may represent the missing player between endothelial damage and uremia-related CVI.…”