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Open Access Original investigation

The effects of low-dose Nepsilon-(carboxymethyl)lysine (CML) and Nepsilon-(carboxyethyl)lysine (CEL), two main glycation free adducts considered as potential uremic toxins, on endothelial progenitor cell function

Jinzhou Zhu1, Ke Yang2, Yajun Jing2, Run Du1, Zhenbin Zhu1, Lin Lu12 and Ruiyan Zhang1*

Author Affiliations

1 Department of Cardiology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

2 Institute of Cardiovascular Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

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Cardiovascular Diabetology 2012, 11:90  doi:10.1186/1475-2840-11-90

Published: 1 August 2012

Abstract

Background

Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD). Endothelial progenitor cell (EPCs) dysfunction plays a key role in this pathogenesis. Uremic retention toxins have been reported to be in associated with EPC dysfunction. Advanced glycation end-products (AGEs) free adducts, including Nepsilon-(carboxymethyl)lysine (CML) and Nepsilon-(carboxyethyl)lysine (CEL), are formed by physiological proteolysis of AGEs and released into plasma for urinary excretion. They are retained in CKD patients and are considered to be potential uremic toxins. Though AGEs have been demonstrated to impair EPC function in various ways, the effect of AGE free adducts on EPC function has not been studied. Thus, we examined the role of CML and CEL in the regulation of growth-factor-dependent function in cultured human EPCs and the mechanisms by which they may affect EPC function.

Methods

Late outgrowth EPCs were incubated with different concentrations of CML or CEL for up to 72 hours. Cell proliferation was determined using WST-1 and BrdU assays. Cell apoptosis was tested with annexin V staining. Migration and tube formation assays were used to evaluate EPC function.

Results

Though CML and CEL were determined to have anti-proliferative effects on EPCs, cells treated with concentrations of CML and CEL in the range found in CKD patients had no observable impairment on migration or tube formation. CML and CEL did not induce EPC apoptosis. The reduced growth response was accompanied by significantly less phosphorylation of mitogen-activated protein kinases (MAPKs).

Conclusions

Our study revealed that CML and CEL at uremic concentrations have low biological toxicity when separately tested. The biologic effects of AGE free adducts on the cardiovascular system merit further study.

Keywords:
Endothelial progenitor cells; Mitogen-activated protein kinases; Nϵ-(carboxyethyl)lysine; Nϵ-(carboxymethyl)lysine; Uremic toxins