The role of soluble receptor for advanced glycation end-products (sRAGE) in the general population and patients with diabetes mellitus with a focus on renal function and overall outcome

Isoforms of the receptor for advanced glycation end-product (RAGE) protein, which lack the transmembrane and the signaling (soluble RAGE or sRAGE) domains are hypothesized to counteract the detrimental action of the full-length receptor by acting as a decoy, and they provide a potential tool to treat RAGE-associated diseases. Multiple studies have explored the relationship between sRAGE and endogenous secretory RAGE and its polymorphism and obesity, metabolic syndrome, atherosclerosis, kidney function, and increased mortality in the general population. In addition, sRAGE may be a key player in the pathogenesis of diabetes mellitus and its microvascular (e.g. kidney disease) as well as macrovascular (e.g. cardiovascular disease) complications. In this review, we focus on the role of sRAGE as a biomarker in these specific areas. As there is a lack of an underlying unifying hypothesis about how sRAGE changes according to the disease condition or risk factor, there is a call to incorporate all three players of the AGE-RAGE axis into a new universal biomarker/risk marker: (AGE + RAGE)/sRAGE. However, the measurement of RAGE in humans is not practical as it is a cell-bound receptor for which tissue is required for analysis. A high AGE/sRAGE ratio may be a valuable alternative and practical universal biomarker/risk marker for diseases associated with the AGE-RAGE axis, irrespective of low or high serum sRAGE concentrations.