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.

晚期糖基化终末产物受体（receptor for advanced glycation end-product, RAGE）的缺失跨膜结构域与信号结构域的同工型，即可溶性RAGE（soluble RAGE, sRAGE），被认为可通过充当诱饵受体抵消全长受体的有害作用，为治疗RAGE相关疾病提供了潜在干预手段。多项研究已探讨了sRAGE与内源性分泌型RAGE的关联，及其基因多态性与肥胖、代谢综合征、动脉粥样硬化、肾功能异常及普通人群死亡率升高之间的关系。此外，sRAGE可能在糖尿病及其微血管并发症（如肾病）与大血管并发症（如心血管疾病）的发病机制中扮演关键角色。本综述聚焦于sRAGE在上述特定领域作为生物标志物的作用。由于目前尚无统一假说阐释sRAGE随疾病状态或危险因素的变化规律，学界呼吁将晚期糖基化终末产物-RAGE（AGE-RAGE）轴的三类组分整合为新型通用生物标志物/风险标志物：(AGE + RAGE)/sRAGE。然而，由于RAGE为细胞结合型受体，需获取组织样本方可开展检测，因此在人体中检测RAGE并不具备实用性。无论血清sRAGE浓度高低，高AGE/sRAGE比值或可成为AGE-RAGE轴相关疾病极具价值且实用的通用生物标志物/风险标志物。