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Kétszeri,M.
The role of microRNA-142-3p in uremic vascular media calcification
PhD-Studium (Doctor of Philosophy); Humanmedizin; [Dissertation] Medical University of Graz;2019. pp.79 [OPEN ACCESS]
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Authors Med Uni Graz:
Advisor:: Eller Kathrin; Eller Philipp; Rosenkranz Alexander
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Abstract:: Introduction: Chronic kidney disease (CKD) is strongly associated with a high burden of cardiovascular morbidity and mortality. There is also emerging evidence that different microRNAs (miRs) play relevant roles in the pathogenesis of CKD and the consequent vascular disease. Therefore, we aimed to characterize the putative role of microRNAs in uremic vascular remodelling and endothelial dysfunction. Methods: We investigated the expression pattern of miRs in two independent end-stage renal disease (ESRD) cohorts and in the animal model of uremic DBA/2 mice via quantitative RT-PCR. Moreover, DBA/2 mice were treated with intravenous injections of synthetic miR-142-3p mimic and were analysed for functional and morphological vascular changes by histology, ELISA, Western blot, mass spectrometry and wire myography. Results: The expression pattern of several miRs was regulated in ESRD patients and was reversible after kidney transplantation. Out of the tested miRs, only blood miR-142-3p was negatively associated with carotid-femoral pulsewave velocity in CKD 5D patients. We validated these findings in a murine uremic model and found similar suppression of miR-142-3p as well as decreased acetylcholine-mediated vascular relaxation of the aorta. Therefore, we designed experiments to restore bioavailability of aortic miR-142-3p in vivo via intravenous injection of synthetic miR-142-3p mimic. This intervention restored acetylcholine-mediated vascular relaxation. Conclusion: Taken together, we provide compelling evidence, both in humans and in mice, that miR-142-3p constitutes a potential pharmacological agent to prevent endothelial dysfunction and increased arterial stiffness in ESRD.