Increased Plasma S100A12 (EN-RAGE) Levels in Hemodialysis Patients with Atherosclerosis

Abstract

Background: S100A12, also known as EN-RAGE (extracellular newly identified receptor for advanced glycation end products binding protein) is a ligand for RAGE, and has been proposed to contribute to the development of atherosclerosis. In this study, we examined the plasma S100A12 concentration in patients with ESRD and undergoing hemodialysis (HD) and evaluated the relation between S100A12 level and carotid intimal media thickness (IMT) by ultrasound. Methods: We measured plasma S100A12 concentration in 72 HD patients and 42 control subjects. IMT of the carotid artery was measured by high-resolution B-mode ultrasonography in 46 HD patients. Results: The mean plasma S100A12 level was 2.3-fold higher in HD patients than in control subjects (25.0 ± 2.32 vs. 10.7 ± 0.97 ng/ml, p < 0.001). Stepwise multiple regression analysis identified circulating white blood cell count as a positive independent determinant and total cholesterol and serum albumin levels as negative independent determinants of plasma S100A12 concentration. The maximum IMT was positively correlated with plasma S100A12 level. Stepwise multiple regression analysis also identified plasma S100A12 as a significant independent determinant of the maximum IMT. Conclusion: These findings suggest that S100A12 protein is involved in the acceleration of atherosclerosis in HD patients.

Calcitriol Treatment Increases Serum Levels of the Soluble Receptor of Advanced Glycation End Products in Hemodialysis Patients with Secondary Hyperparathyroidism

“…However, we did not find a reduction in EN-RAGE levels after calcitriol treatment; in fact, we observed an increase. The sRAGE levels we detected were similar to those in previous reports (Kalousova et al 2006;Nakashima et al 2010), although our EN-RAGE levels were relatively higher than those previously reported (Mori et al 2009;Nakashima et al 2010;Shiotsu et al 2011;Zakiyanov et al 2011). The precise reason for such discrepancy is not clear.…”

“…Elevated plasma EN-RAGE concentrations have been positively associated with carotid artery atherosclerosis (Mori et al 2009;Kim et al 2012), and Nakashima et al showed that EN-RAGE concentration was a direct predictor of allcause and CVD-related mortality, even after adjusting for confounders (Nakashima et al 2010). However, we did not find a reduction in EN-RAGE levels after calcitriol treatment; in fact, we observed an increase.…”

“…We also hypothesized that SHP status would affect EN-RAGE levels, as the positive relationship between 1,25D and sRAGE and the inverse relationship between sRAGE and EN-RAGE were discovered after calcitriol treatment, although this warrants further investigation. Because the observed increase in sRAGE and reduction in EN-RAGE may be related to CVD, hypertension, and atherosclerosis in patients with ESRD (Mori et al 2009;Nakashima et al 2010;Shiotsu et al 2011;Wu et al 2011;Kim et al 2012), the previously unreported relationship between SHP and EN-RAGE levels merits additional study.…”

“…In contrast to sRAGE, extracellular RAGE-binding protein (EN-RAGE), also known as S100A12, acts as pro-inflammatory ligands for RAGE and contributes to occur the atherosclerotic vascular complications (Yang et al 2001;Mahajan et al 2009;Nakashima et al 2010). Mori et al (2009) showed that EN-RAGE is involved in the acceleration of atherosclerosis in HD patients.…”

Effect of Circulating Soluble Receptor for Advanced Glycation End Products (sRAGE) and the Proinflammatory RAGE Ligand (EN-RAGE, S100A12) on Mortality in Hemodialysis Patients

“…In human coronary atherosclerotic plaques, a strong expression of S100A12 in smooth muscle cells and macrophages was reported (20), involving altogether S100A12 binding in the development of atherosclerosis. Similar to sRAGE levels, S100A12 levels are also elevated in patients with CKD and positively associated with IMT (21).…”