Download or read book The Role of Non-coding RNAs in Vascular Damage in Hypertension and CKD written by Kugeng Huo and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Hypertension and chronic kidney disease (CKD) are two of the most prevalent global health concerns that account for millions of deaths per year. They are both associated with vascular damage that is characterized by vascular remodeling and stiffening, as well as endothelial dysfunction, which contribute to further development of the disease and lead to end organ damage. MicroRNAs (miRNAs) are important non-coding RNA regulators of gene expression that cause translational repression and transcript degradation upon binding to their target mRNAs. miRNAs have been demonstrated to be associated with hypertension and CKD, and play a critical role in vascular cell development and function. However, their role in vascular damage is still poorly studied. We hypothesized that vascular and circulating miRNAs are dysregulated in hypertension and CKD; the dysregulation of vascular miRNAs is a key driving force of pathological gene expression changes that contribute to vascular damage; key dysregulated vascular miRNAs are potential therapeutic targets and key dysregulated circulating miRNAs are potential biomarkers for vascular damage in hypertension and CKD. The thesis contains 3 studies testing our hypotheses.In the first study, we profiled miRNAs using RNA sequencing in mesenteric arteries of mice infused or not with angiotensin (Ang) II for 7 or 14 days. We observed that both 7-day and 14-day Ang II infusion induced blood pressure (BP) elevation, oxidative stress and vascular stiffening, whereas only 14-day Ang II-infusion caused endothelial dysfunction and vascular remodeling. Using a candidate approach, we have identified miR-431-5p and its target Ets Homologous Factor (Ehf) as key regulators in Ang II-induced hypertension and vascular damage. miR-431-5p and Ehf were up- and down-regulated by 14-day Ang II-infusion, respectively, and were both correlated with BP. We demonstrated that miR-431-5p targets EHF in human aortic vascular smooth muscle cells, where EHF down-regulates collagen type I alpha 1 chain (Col1a1), and miR-382-5p. Intravenous injection of miR-431-5p inhibitors down-regulated miR-431-5p, Col1a1 and miR-382-5p, and up-regulated Ehf in mesenteric arteries, delayed BP elevation and reduced vascular damage in mice infused with Ang II for 14 days.In the second study, we profiled miRNAs as above but this time in small arteries dissected from subcutaneous gluteal biopsies performed in normotensive, hypertensive and CKD subjects to identify differentially expressed vascular miRNAs. Combined with the data from the first study, we found a common miRNA, miR-145-3p, that was down-regulated in both 7-day Ang II-infused mice and CKD patients. Whether miR-145-3p mediates vascular damage in Ang II-induced hypertension model and CKD remains to be elucidated.In the third study, we profiled circulating miRNAs from plasma of the same cohort of normotensive hypertensive and CKD subjects as in the second study. We identified and validated 4 differentially expressed miRNAs, let-7g-5p, miR-26a-5p, miR-191-5p and let-7b-5p, among which let-7g-5p was correlated with estimated glomerular filtration rate. We also found a correlation between circulating let-7g-5p and genes that were differentially expressed in small arteries of CKD patients.To summarize, miR-431-5p and its target Ehf are potential important regulators in the pathophysiology of vascular damage in hypertension, and may serve as novel therapeutic targets in the clinic. miR-145-3p may play a role in the development of Ang II-induced and CKD-associated vascular injury. Let-7g-5p has potential clinical value to serve as a biomarker for vascular damage in CKD." --