[Frontiers in Bioscience S3, 1478-1485, June 1, 2011] 1478 Possible involvement of the (pro)renin receptor-dependent system in the development of insulin resistance Kazi Rafiq 1 , Hirofumi Hitomi 1 , Daisuke Nakano 1 , Atsuhiro Ichihara 2 , Akira Nishiyama 1 1 Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan, 2 anti-Aging Medicine and Endocrinology and Internal Medicine, Keio University School of Medicine, Tokyo, Japan TABLE OF CONTENTS 1. Abstract 2. Introduction 3. RAS and Insulin Resistance 4. Insulin Resistance and the (Pro)renin Receptor-dependent System 5. Clinical Studies 6. Conclusions 7. References 1. ABSTRACT It is widely acknowledged that activation of the renin-angiotensin system impairs insulin sensitivity. Pharmacological inhibition of the (pro)renin receptor- dependent system has shown beneficial effects in diabetic nephropathy, retinopathy and hypertensive cardiac damage in animal models. Previously, we showed that fructose feeding stimulated nonproteolytic activation of prorenin and subsequent production of angiotensin II in skeletal muscle in rats, and that inhibition of the (pro)renin receptor-dependent system improved the development of fructose feeding-induced insulin resistance. In addition, our current preliminary study suggests that local angiotensin II generation in skeletal muscle and adipose tissues induced by nonproteolytic activation of prorenin is involved in the development of spontaneous insulin resistance in type 2 diabetic rats. In this review, we will briefly summarize the possible contribution of the (pro)renin receptor-dependent system to the pathogenesis of insulin resistance, with a focus on how the nonproteolytic activation of prorenin contributes to the development of insulin resistance. 2. INTRODUCTION A growing body of evidence suggests that activation of the renin-angiotensin system (RAS) impairs insulin sensitivity (1), and that hyperinsulinemia and insulin resistance promote the development of cardiovascular disorders (2, 3). In addition, clinical studies have shown that treatments with RAS inhibitors, such as angiotensin (Ang)-converting enzyme (ACE) inhibitors (4), Ang II type 1 receptor blockers (ARBs) (5) and a direct renin inhibitor (DRI) (6), prevent the development of insulin resistance in hypertensive patients, indicating that ACE, Ang II and renin contribute to the development of insulin resistance. On the other hand, it is also acknowledged that tissue RAS, such as the intrarenal Ang II levels, are regulated in a manner distinct from the systemic RAS (7). However, the mechanisms by which tissue RAS is activated during the development of insulin resistance are still unclear. Prorenin, the enzymatically inactive precursor of renin, is expressed in various tissues (8), and has an amino-terminal prosegment that is thought to cover the