Endogenous secretory receptor for advanced glycation end-products and cardiovascular disease in end-stage renal disease.

Abstract

The receptor for advanced glycation end-products (RAGE) is involved in microvascular and macrovascular complications in diabetes. The expression of RAGE is up-regulated in atherosclerotic plaques of diabetic animals, and the augmentation of atherosclerosis in diabetic mice is inhibited by the competition of RAGE. An endogenous secretory RAGE (esRAGE) was identified as a novel splice variant carrying all of the extracellular domains, but devoid of the transmembrane and intracytoplasmic domains. The esRAGE is released from the cells, to bind advanced glycation end-products, and this is capable of neutralizing the actions of advanced glycation end-products on endothelial cells in culture. The adenoviral overexpression of esRAGE restores the impairment of vascular dysfunction in diabetes, suggesting that esRAGE may be an important inhibitor of RAGE signaling in vivo, and may be useful for the prevention of diabetic vascular complications. In 203 age-matched and sex-matched type 2 diabetic and 134 nondiabetic subjects, plasma esRAGE levels were inversely associated with carotid or femoral atherosclerosis. In patients with end-stage renal disease (ESRD), plasma esRAGE levels are higher than in those without ESRD. In a cohort of 206 patients (including 171 nondiabetic patients) with chronic renal failure who were followed for a median of 111 months, the cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly higher in subjects in the lowest tertile of plasma esRAGE than in those in the middle or highest tertile. Compared with the lowest tertile of plasma esRAGE, the hazards ratios for the highest and middle tertile were 0.40 (95% confidence interval, 0.18 to 0.89) and 0.26 (95% confidence interval, 0.10 to 0.66), respectively. The higher risk at the lower level of esRAGE was still significant even after adjustment for body mass index, hypertension, dyslipidemia, and vascular complications, and was confounded only by age and diabetes. Thus, we postulate that plasma esRAGE is a potential protective factor and a novel biomarker against the occurrence of cardiovascular disease in ESRD.