Increased Plasma S100A12 (EN-RAGE) Levels in Patients with Type 2 Diabetes

Abstract

S100A12, also called EN-RAGE (extracellular newly identified receptor for advanced glycation end products binding protein) or calcium-binding protein in amniotic fluid-1, is a ligand for RAGE. It has been shown that S100A12 induces adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in the vascular endothelial cell and mediates migration and activation of monocytes/macrophages through RAGE binding and that infusion of lipopolysaccharide into mice causes time-dependent increase of S100A12 in the plasma. Therefore, circulating S100A12 protein may be involved in chronic inflammation in the atherosclerotic lesion. In this study, we developed an ELISA system that uses specific monoclonal antibodies against recombinant human S100A12 to measure plasma S100A12 levels in patients with diabetes. On using our S100A12 ELISA system, the coefficients of variation of intra- and interassay were less than 4 and 9%, respectively. The analytical lower detection limit was 0.2 ng/ml. When plasma S100A12 levels were measured by this system, the concentrations were more than twice as high in the patients with diabetes, compared with those without. Using univariate analysis in all subjects, plasma S100A12 concentrations correlated with hemoglobin A1c, fasting glucose, high-sensitivity C-reactive protein and white blood cell count. Stepwise multiple regression analyses, however, revealed that only white blood cell count and hemoglobin A1c remained significant independent determinants of plasma S100A12 concentration. These results suggest that plasma S100A12 protein levels are regulated by factors related to subclinical inflammation and glucose control in patients with type 2 diabetes.

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

“…However, our observation opposes the reports in individuals with type 2 diabetes, where S100A12 was increased (29,30) and sRAGE decreased (30) as compared with those in healthy patients. Also, sRAGE was significantly lower in patients with angiographically proven coronary artery disease than in age-matched healthy controls (31).…”

The expression of advanced glycation endproduct receptors in rpe cells associated with basal deposits in human maculas

“…β-amyloid is implicated in the pathogenesis of Alzheimer's disease (Schmidt et al, 2001) and has been localized to drusen Dentchev et al, 2003). The S100/calgranulins are pro-inflammatory polypeptides which have been associated with a number of chronic diseases that have an inflammatory component, such as atherosclerosis, Alzheimer's disease, and diabetes mellitus (Sakaguchi et al, 2003;Kosaki et al, 2004;Lue et al, 2005). Accumulation of RAGE ligands and upregulation of RAGE results in sustained cellular activation that promotes disease progression (Schmidt et al, 2001).…”

Chronic Inflammation and S100A12/ Receptor for Advanced Glycation Endproducts Axis: A Novel Risk Factor for Cardiovascular Disease in Patients with Chronic Kidney Disease?

“…The binding of S100 proteins, including calgranulins S100A6 and S100A18, is still debated (Goyette and Geczy, 2010). Engagement of the extracellular domain of the RAGE membrane by calcium-bound S100A12 activates intracellular signal cascades, including MAP kinase and NF-κB, which induce cytokine secretion (e.g., TNF-and IL-1 ), and expression of adhesion molecules (e.g., ICAM-1 and VCAM-1), and thereby mediate their pro-inflammatory effects on lymphocytes, endothelial cells, neutrophils, and mononuclear phagocytes (Yang et al, 2001), leading to the development of several chronic inflammation such as asthmatic lung , rheumatoid synovuim (Yang et al, 2001), inflamed mucosa in inflammatory bowel disease (Leach et al, 2007), diabetes mellitus (Kosaki et al, 2004), and atherosclerosis (Mori et al, 2009). …”