AGEs/RAGE in CKD: irreversible metabolic memory road toward CVD?

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. Mortality from cardiovascular diseases in these patients is approximately 9% per year, which is about 30 times the risk in the general population. So far, intensive interventions to the general risk factors, such as high LDL-cholesterol or C-reactive protein, have not been successful in improving their cardiovascular outcomes, suggesting that the beneficial effect of risk reduction may be overwhelmed by accumulated risk memorized by long-term exposure to oxidative stress during the progression of renal failure. In this review, we propose that this irreversible memory effect in renal failure may be mediated by advanced glycation end-products (AGEs). The generation of AGEs has been implicated to be deeply associated with increased oxidative stress. 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. Several lines of evidence suggest that AGEs/RAGE axis can profoundly be involved in cardiovascular diseases. Recent advances in AGEs and RAGE measurements led us to be capable of understanding more about the role of AGEs/RAGE axis as a risk for cardiovascular diseases in patients with renal failure. AGEs/RAGE axis could be a crucial mediator of oxidative stress in renal failure. RAGE could be not only a useful biomarker, but also a potentially therapeutic target to overcome the accumulated adverse metabolic memory in renal failure.