**7. Summary**

108 Biomedical Science, Engineering and Technology

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

It would be essential to determine whether currently available pharmacological agents can regulate plasma sRAGE or esRAGE. Potential agents that may affect circulating soluble RAGE include the angiotensin-converting enzyme (ACE) inhibitor 146, thiazolidinediones (TZD) 147 and statins 148-150, which are known to modulate the AGEs-RAGE system in culture. Forbes et al 146 showed that inhibition of angiotensin-converting enzyme (ACE) in rats increased renal expression of sRAGE, and that this was associated with decreases in expression of renal full-length RAGE protein. They also showed that plasma sRAGE levels were significantly increased by inhibition of ACE in both diabetic rats and in human subjects with type 1 diabetes. Thus, one attractive scenario is that the protective effect of ACE inhibition against progression of renal dysfunction is mediated through regulation of

Tam et al recently reported changes in serum levels of sRAGE and esRAGE in archived serum samples from a previous randomized double-blind placebo-controlled clinical trial that explored the cardiovascular effects of atorvastatin in hypercholesterolemic Chinese type 2 diabetic patients, and found that atorvastatin can increase circulating esRAGE levels 150.

For thiazolidinedione, a randomised, open-label, parallel group study was performed with 64 participants randomised to receive add-on therapy with either rosiglitazone or sulfonylurea to examine the effect on plasma soluble RAGE 151. At 6 months, both rosiglitazone and sulfonylurea resulted in a significant reduction in HbA1c, fasting glucose and AGE. However, significant increases in total sRAGE and esRAGE were only seen in the rosiglitazone group. In a recent study in type 2 diabetes mellitus patients, pioglitazone, but not rosiglitazone, significantly raised sRAGE levels 152, suggesting that all thiazolidinedione may not act similarly. Nevertheless, thiazolidinedione could be one promising candidate which increase circulating levels of esRAGE and sRAGE, and RAGE/soluble RAGE regulation may be involved in thiazolidinedione-mediated improvement of insulin resistance. Finally, we have started the randomized clinical trial comparing the effect of

potential targets for therapeutic application of soluble RAGE.

**A. Angiotensin-converting enzyme inhibitor** 

RAGE versus soluble RAGE production.

**B. Statin** 

**C. Thiazolidinedione** 

**6.3 Pharmacological agents regulate circulating sRAGE and esRAGE** 

The findings discussed here implicated pivotal role of RAGE system in initiation and progression of metabolic syndrome, insulin resistance and atherosclerosis. Provided that continuous RAGE activation represents the concept of "metabolic memory", metabolic syndrome might be conceptualized as memorized long-term subtle inflammation and oxidative stress using RAGE as an inflammatory scaffold. In this system, endogenous inflammatory RAGE ligands may be profoundly involved (Figure 7). Further, sRAGE or esRAGE could serve as a biomarker as well as a therapeutic target for these disease conditions. Obviously there are many missing parts to be veiled to further understand the role of RAGE/soluble RAGE axis in metabolic syndrome and insulin resistance. However, we believe our findings and this concept would open up a new research field which could further precede our understanding of the RAGE biology.

Fig. 7. Metabolic syndrome may be an aspect of "metabolic memory" conceptualized as prolonged RAGE activation through subclinical information.
