RAGE is also reported to have a self-downregulation system. As an example of a pathway for the auto-downregulation of RAGE-mediated cellular activation, the binding of HMGB1 to RAGE induces an intracellular signal transduction, as well as RAGE shedding by a disintegrin and metalloproteinase domain-containing protein 1073. The cleavage of the membrane-bound full-length signal-transducing RAGE yields sRAGE, which could work as a decoy receptor against ligand–RAGE interactions. In the strict sense of the word, sRAGE is a heterogeneous population of total sRAGE proteins, including the soluble splice variants of RAGE, as well as the proteinase-cleaved forms of membrane-bound RAGE and the soluble splice variants (Figure 2)74. Endogenous secretory RAGE (esRAGE) is one of the major splice variants of RAGE (Figure 4); it exists in the circulation, and is widely distributed throughout the cell surface and cytoplasm of neurons, endothelial cells, pneumocytes, mesothelium, pancreatic β-cells, monocytes, macrophages, salivary glands, digestive tracts, renal tubules, prostate, skin, thyroid and bronchioles75–77. sRAGE and esRAGE are thought to act locally and systemically as decoy receptors. Reinforcing ectodomain shedding decreases the total amount and expression of signal-transducing RAGE; this reciprocally increases the amount of decoy receptor sRAGE, which can control ligand–RAGE signaling and subsequent cellular and tissue derangement74. sRAGE is also reported to mediate inflammation by directly binding to monocytes under conditions with few ligands, although the mechanism of action is unknown78. Recent clinical studies have focused on the significance of circulating sRAGE or esRAGE in diabetic vascular complications. Findings in both type 1 and 2 diabetic patients are quite conflicting; both inverse and positive correlations are reported in diabetic retinopathy, nephropathy and incident cardiovascular disease events, as well as mortality outcomes74,79–84. There are several reasons why this occurs. First, sRAGE and esRAGE production is inducible; the former is sheddase-dependent, whereas the latter is original RAGE promoter- and splicing-dependent. Second, the presence of renal insufficiency can strongly and positively influence circulating sRAGE and esRAGE levels74. Third, medications might alter sRAGE or esRAGE level.