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

### **A. Angiotensin-converting enzyme inhibitor**

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 RAGE versus soluble RAGE production.

## **B. Statin**

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.

### **C. Thiazolidinedione**

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 pioglitazone with glimepiride on plasma sRAGE and esRAGE, expression of RAGE on peripheral mononuclear cells, and RAGE shedase gene expression in type 2 diabetic patients (UMIN000002055). This study will be of particular importance to understand the regulatory mechanisms of sRAGE and esRAGE in clinical setting.
