Abstract

Background: Uremic vascular calcification (UVC) is reminiscent of osteogenesis and apoptosis in vascular smooth muscle cell (VSMC). We aimed to identify how circulating procalcific particles dramatically leak into VSMC layer in human tissue models of vascular rings.Methods: According to baseline estimated glomerular filtration rate (eGFR), patients following lower extremity amputation were divided into three groups: normal renal function (eGFR ≧ 60 ml/min), mild-to-moderate (15 ml/min < eGFR ≧ 60 ml/min) and severe chronic kidney disease (CKD) (eGFR ≦ 15 ml/min). Arterial specimens with immunohistochemistry stain were quantitatively analyzed for UVC, internal elastic lamina (EL) disruption, α-SMA, osteogenesis, apoptosis, and oxidative injury. Correlations among UVC severity, eGFR, EL disruption, osteogenesis, and oxidative injury were investigated.Results: CKD arteries were associated with eGFR-dependent EL disruption corresponding to UVC severity. CKD arteries exhibited lower α-SMA, higher expressions of caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), indicative of contractile VSMC loss, and apoptosis. Enhanced expressions of alkaline phosphatase and Runx2 were presented in VSMCs of CKD arteries, indicative of osteogenic differentiation. Above eGFR-dependent UVC and EL disruption correlated expressions of 8-hydroxy-2′-deoxyguanosine (8-OHdG), indicating oxidative EL injury promoted procalcific processes.Conclusions: Circulating uremic milieu triggers vascular oxidative stress, leading to progressive internal EL disruption as a key event in disabling VSMC defense mechanisms and catastrophic mineral ion influx into VSMC layer. Oxidative EL injury begins in early CKD, corresponding with active VSMC re-programming, apoptosis, and ultimately irremediable UVC. In light of this, therapeutic strategies targeting oxidative tissue injury might be of vital importance to hinder the progression of UVC related cardiovascular events.

Highlights

  • Cardiovascular diseases (CVD) still top the list as the leading causes of death in patients with chronic kidney disease (CKD) worldwide [1, 2]

  • Our data demonstrated elevated plasma concentrations of non-hepatic alkaline phosphatase (ALP), calcium-phosphate product, and Creactive protein (CRP) were in parallel with estimated glomerular filtration rate (eGFR) decline among patients with amputations

  • We aimed to provide the evidence that the internal Elastic Lamina (EL) in CKD arteries were profoundly eroded in uremic milieu, leading to a leaky intima

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Summary

Introduction

Cardiovascular diseases (CVD) still top the list as the leading causes of death in patients with chronic kidney disease (CKD) worldwide [1, 2]. The reasons why ESRD patients are at particular risk for UVC are intricate, including chronic mineral dysregulation [9], calcium-based therapies, pro-oxidant and pro-inflammatory effects of uremic toxins, active process of osteogenesis in vascular smooth muscle cells (VSMC) and passive process of mineral deposition in extracellular matrix (ECM) [10]. Given comprehensive pictures of UVC remain elusive in cell models of in vitro research, we aimed to investigate the association between UVC and oxidative tissue injury using human models of vascular rings in this study. We aimed to identify how circulating procalcific particles dramatically leak into VSMC layer in human tissue models of vascular rings

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