Elevation of circulating endothelial microparticles in patients with chronic renal failure

Abstract

Summary. Background: Chronic renal failure patients are at high risk of cardiovascular events and display endothelial dysfunction, a critical element in the pathogenesis of atherosclerosis. Upon activation, the endothelium sheds microparticles, considered as markers of endothelial dysfunction that also behave as vectors of bioactive molecules. Aim: To measure plasma levels of endothelial microparticles (EMPs) in chronic renal failure patients (CRF), either undialyzed or hemodialyzed (HD), and to investigate the ability of uremic toxins to induce EMP release in vitro. Methods: Circulating EMPs were numerated by flow cytometry, after staining of platelet-free plasma with phycoerythrin (PE)-conjugated anti-CD144 (CD144+ EMP) or anti-CD146 (CD146+ EMP) monoclonal antibodies. Platelet MP (CD41+ PMP), leukocyte MP (CD45+ leukocyte microparticles (LMP)), and annexin-V+ MPs were also counted. In parallel, MPs were counted in supernatant of human umbilical vein endothelial cells incubated with uremic toxins [oxalate, indoxyl sulfate, p-cresol, and homocysteine (Hcy)], at concentrations found in patients. Results and conclusions: CD144+ EMP and CD146+ EMP levels were significantly higher in CRF and HD patients than in healthy subjects. Furthermore, annexin-V+ MPs were elevated in both groups of uremic patients, and CD41+ PMP and CD45+ LMP were increased in CRF and HD patients, respectively. In vitro, p-cresol and indoxyl sulfate significantly increased both CD146+ and annexin-V+ EMP release. Increased levels of circulating EMP in CRF and HD patients represent a new marker of endothelial dysfunction in uremia. The ability of p-cresol and indoxyl sulfate to increase EMP release in vitro suggests that specific uremic factors may be involved in EMP elevation in patients.

Oral adsorbent AST-120 ameliorates endothelial dysfunction independent of renal function in rats with subtotal nephrectomy

“…However, some in vitro studies have revealed the toxicity of IS in vascular cells. 14,33,34 In addition, oxidative stress induced by IS may damage vascular cells in an indirect manner. 26,27,36 Therefore, IS accumulation is considered to be one of the pathogenic mechanisms causing endothelial dysfunction in patients with CKD.…”

“…33,34 IS inhibited endothelial proliferation and wound repair, and increased endothelial microparticles in human umbilical vein endothelial cells (HUVEC). In this study, we showed that the endothelium-dependent aortic response correlated significantly with serum IS levels.…”

Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis

“…78 In many such diseases, the number of circulating MPs is directly correlated with the severity of the associated chronic renal failure. 79 Pathogenetic effects of circulating membrane particles in CRD have yet to be completely defined. It is possible that they are involved in promoting accelerated arterial calcification and sclerosis, as seen, not only in the affected kidneys but also at multiple sites in arteries throughout the body.…”

Circulating Microparticles

“…32 Although the question of whether circulating levels of endothelial MPs cause or result from endothelial dysfunction is still much debated, in vitro evidence indicates that the augmented plasma levels of endothelial MPs, as observed in patients with end-stage renal diseases, could result from endothelial injury or apoptosis. 32,73 Cytokines, activated platelets, or oxidized low-density lipoprotein could play a role as well. However, the in vivo stimuli of endothelial vesiculation in patients with cardiovascular diseases remain mostly unknown so far.…”