Abstract
Patients with CKD have abnormal vascular remodeling that is a risk factor for cardiovascular disease. MicroRNAs (miRNAs) control mRNA expression intracellularly and are secreted into the circulation; three miRNAs (miR-125b, miR-145 and miR-155) are known to alter vascular smooth muscle cell (VSMC) proliferation and differentiation. We measured these vascular miRNAs in blood from 90 patients with CKD and found decreased circulating levels with progressive loss of eGFR by multivariate analyses. Expression of these vascular miRNAs miR-125b, miR-145, and miR-155 was decreased in the thoracic aorta in CKD rats compared to normal rats, with concordant changes in target genes of RUNX2, angiotensin II type I receptor (AT1R), and myocardin. Furthermore, the expression of miR-155 was negatively correlated with the quantity of calcification in the aorta, a process known to be preceded by vascular de-differentiation in these animals. We then examined the mechanisms of miRNA regulation in primary VSMC and found decreased expression of miR-125b, 145, and 155 in VSMC from rats with CKD compared to normal littermates but no alteration in DROSHA or DICER, indicating that the low levels of expression is not due to altered intracellular processing. Finally, overexpression of miR-155 in VSMC from CKD rats inhibited AT1R expression and decreased cellular proliferation supporting a direct effect of miR-155 on VSMC. In conclusion, we have found ex vivo and in vitro evidence for decreased expression of these vascular miRNA in CKD, suggesting that alterations in miRNAs may lead to the synthetic state of VSMC found in CKD. The decreased levels in the circulation may reflect decreased vascular release but more studies are needed to confirm this relationship.
Highlights
MicroRNAs are small, non-coding RNAs that function to regulate messenger RNAs post-transcriptionally by degrading or repressing mRNA. miRNAs play a critical function during development through effects on cell proliferation, differentiation, and apoptosis [1,2]
In the present study we demonstrate that these vascular miRNAs are decreased in the serum of patients with Chronic Kidney Disease (CKD) and hemodialysis patients compared to controls and are potential biomarkers
We further examined the mechanism by which these miRNA of vascular origin are decreased by comparing expression and regulation in vascular smooth muscle cell (VSMC) from CKD rats compared to normal littermates
Summary
MicroRNAs (miRNAs) are small (approximately 22 nucleotide), non-coding RNAs that function to regulate messenger RNAs (mRNAs) post-transcriptionally by degrading or repressing mRNA. miRNAs play a critical function during development through effects on cell proliferation, differentiation, and apoptosis [1,2]. MicroRNAs (miRNAs) are small (approximately 22 nucleotide), non-coding RNAs that function to regulate messenger RNAs (mRNAs) post-transcriptionally by degrading or repressing mRNA. The miRNA are further processed in the nucleus through activity of DROSHA, an RNAse III, into precursor miRNA that are transported into the cytoplasm. There they are cleaved by DICER to generate miRNA that are incorporated into the RNA-induced silencing complex (RISC) to form a RISC-miRNA complex that represses mRNA transcription or enhances mRNA degradation[3]. Each miRNA may affect multiple mRNA, and each mRNA may have multiple miRNA regulating its transcriptional activity [4,5]. In non-CKD patients with cardiovascular disease, miR-145 and miR-155 were found to be lower in patients with coronary artery disease than in those without [7]
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