Cardiovascular Complications in Renal Failure: Implications of Advanced Glycation End Products and Their Receptor RAGE

Abstract

Cardiovascular disease is the major cause of death in patients with renal insufficiency, accounting for 50% of all deaths in renal replacement therapy patients and in recipients of renal transplants. Mortality from cardiovascular diseases in patients with renal failure is approximately 9% per year, which is about 30 times the risk in the general population. Evidence has emerged pointing to a potential role of oxidative stress in generation of advanced glycation end products (AGEs) in patients with end stage renal disease (ESRD). Moreover, interaction of the receptor for AGEs (RAGE) with AGEs leads to crucial biomedical pathway, generating intracellular oxidative stress and inflammatory mediators, which could result in further amplification of the pathway involved in AGE generation. AGEs and RAGE can profoundly be involved in cardiovascular diseases through regulation of (a) atherogenesis, (b) angiogenic response, (c) vascular injury, and (d) inflammatory response. Recently, numerous truncated forms of RAGE have been described, and the C-terminally truncated soluble form of RAGE has received much attention. Soluble RAGE consists of several forms including endogenous secretory RAGE (esRAGE), which is a spliced variant of RAGE, and a shedded form derived from cell surface RAGE. These heterogeneous forms of soluble RAGE, carrying all of the extracellular domains but devoid of the transmembrane and intracytoplasmic domains, bind ligands including AGEs and are capable of antagonizing RAGE signaling in vitro and in vivo. Enzyme-linked immunosorbent assay (ELISA) systems to measure plasma esRAGE and total soluble RAGE have been developed, and the pathophysiological roles of soluble RAGE have begun to be unveiled clinically. In this chapter, we will summarize the recent findings of AGEs/RAGE/soluble RAGE axis as a crucial mediator of oxidative stress and cardiovascular disease and discuss their potential usefulness as therapeutic targets and biomarkers for the disease.