**6.1 Soluble RAGE as a therapeutic tool in animal disease models**

Potential usefulness of soluble RAGE for prevention and treatment of inflammatory diseases has been demonstrated in many animal models. Blockade of RAGE by administration of genetically engineered sRAGE successfully prevented the development of micro- 132, 133 and macrovascular complications in diabetes 134-136. We have also shown that adenoviral overexpression of esRAGE successfully restored the impaired angiogenic response in diabetic mice 101. Sakaguchi et al found that administration of sRAGE markedly suppressed neointimal formation following arterial injury in non-diabetic mice 137. Soluble RAGE has also been shown to effectively prevent the development of diabetes 138, protect against tumor growth and metastasis 58, improve the outcome of colitis 56, restore impaired wound healing 139, and suppress Alzheimer disease-like conditions 140. These effects of soluble RAGE in animal models could be explained by its decoy function, inhibiting RAGE interaction with its proinflammatory ligands, which might be applicable to human diseases as well. Since our findings strongly suggest the role of RAGE in adiposity, metabolic syndrome and atheroslcerosis 16, RAGE/soluble RAGE axis could also be a potential therapeutic target against these pathophysiological conditions.

## **6.2 Potential regulatory mechanisms of circulating soluble RAGE**

So far, limited findings are available regarding the mechanisms of regulation of circulating esRAGE or sRAGE in humans. A tissue microarray technique using a wide variety of adult normal human preparations obtained from surgical and autopsy specimens revealed that esRAGE was widely distributed in tissues, including vascular endothelium, monocyte/macrophage, pneumocytes, and several endocrine organs 141. However, it is unclear at present from which organ or tissue plasma sRAGE or esRAGE originate. Circulating AGEs may be involved in regulation of the secretion or production of soluble RAGE, since AGEs are known to upregulate RAGE expression in vitro 142. esRAGE could be simultaneously upregulated by AGEs and act as a negative feedback loop to compensate for the damaging effects of AGEs. We and others have found positive correlations between plasma sRAGE or esRAGE and AGEs 11, 114-116, 123. Significant positive correlation between plasma esRAGE and pentosidine was observed both in hemodialysis and non-hemodialysis subjects 11. However, plasma CML did not significantly correlated with plasma esRAGE both in hemodialysis and non-hemodialysis subjects. AGEs-mediated regulation of soluble RAGE is also supported by the findings that the suppression of sRAGE expression in diabetic rat kidney is reversed by blockade of AGEs accumulation with alagebrium 143. Other inflammatory mediators, such as S100, tumor necrosis factor α, and C-reactive protein, could also be potential candidates for regulation of the plasma level of soluble RAGE in humans 120, 142, 144. Moreover, Geroldi et al 145 showed that high serum sRAGE is associated with extreme longevity, suggesting that understanding the intrinsic regulation of RAGE and soluble RAGE is important for longevity/anti-aging strategies. Without doubt, further understanding of the regulation of soluble RAGE will be most helpful in delineating potential targets for therapeutic application of soluble RAGE.
