Clinical Relevance of Local Renin Angiotensin Systems

The concept of a “local” renin angiotensin system (RAS) can mean different things to different people. Its main purpose is to differentiate the “local” RAS operating in tissues from the classical “circulating” RAS, but it is difficult to differentiate between the two systems because of their extensive overlap. The circulating RAS comprises kidney-derived renin acting on liver-derived angiotensinogen to generate angiotensin (Ang) I that is converted to Ang II by angiotensin converting enzyme (ACE). However, tissues are the main site of production of angiotensin peptides by the circulating RAS, whereby plasma-derived renin acts on plasmaderived angiotensinogen to generate Ang I, which is converted to Ang II by endothelial ACE (1–4). Local RAS refers to tissue-based mechanisms of Ang peptide formation that operate separately from the circulating RAS. Although many different concepts of local RAS have been described, a key feature is the local synthesis of RAS components including angiotensinogen and enzymes such as renin that cleave angiotensinogen to produce Ang peptides independently of the circulating RAS. ACE and Ang II type 1 (AT1) and type 2 (AT2) receptors are invariably locally synthesized, but these are also components of the circulating RAS. Many other potential components of local RAS have been described that may contribute to tissuespecific mechanisms of Ang peptide formation, and that may either participate in disease processes or contribute to mechanisms that protect from tissue injury. These include the (pro)renin receptor (5), renin-independent mechanisms of Ang peptide generation from Ang(112) (6), intracellular (or intracrine) RAS that may contribute to cardiovascular disease (7, 8), and AT2 receptors (7) and the ACE2/Ang-(1-7)/Mas receptor pathway (6–8) that may mediate therapeutic benefit in cardiovascular disease. In addition, novel Ang peptides with novel pharmacology, including Ang IV, Ang A, alamandine, and angioprotectin (6, 8), have the potential to contribute to disease or to protective mechanisms. Moreover, the brain RAS, including the ACE2/Ang-(17)/Mas receptor and the Ang IV/insulin regulated aminopeptidase pathways may play a role in Alzheimer’s and Parkinson’s diseases (9). Local production of aldosterone may have a pathogenic role (7, 10), ACE, AT2 receptors, Ang-(1-7) and acetyl-Ser-Asp-Lys-Pro may have a role in hematopoiesis (11), and the ACE2/Ang-(17)/Mas receptor pathway may contribute to fetal programing, reproduction, and cancer (6, 12). This short opinion piece discusses the potential clinical relevance of local RAS. The challenge in demonstrating the independence of local from circulating RAS, and the potential interaction of ACE inhibitor and AT1 receptor blocker (ARB) therapies with local RAS are discussed. Attempts to define local RAS that are independent of the circulating RAS have been primarily based on animal models and the clinical relevance of local RAS is uncertain. However, this area of research continues to evolve, and today’s opinions may change as we gain better understanding of how these novel components and mechanisms impact on clinical medicine. HOW CAN LOCAL RAS BE SHOWN TO BE INDEPENDENT OF THE CIRCULATING RAS? As reviewed elsewhere (5–12), many lines of evidence suggest the possibility of local RAS that may operate independently of the circulating RAS and play a pathogenic or protective role. This evidence includes the widespread tissue expression of angiotensinogen, the only known precursor of the Ang peptides and an essential requirement for an independent local RAS (13–16). However, local production of RAS components does not prove their functional significance, and proving their clinical relevance presents many challenges. One approach to study of the role of locally synthesized RAS components is their targeted deletion from specific tissues. This approach has been applied to the kidney. Both clinical experiences with ACE inhibitor and ARB therapies during pregnancy, and ACE, renin, angiotensinogen, and AT1 receptor gene mutation and knockout models demonstrate a critical role for the RAS in renal development and function in animals and humans (17–23). Moreover, ACE inhibition demonstrates a differential regulation of Ang II levels in kidney and blood (24). However, these data do not prove a specific role for the local RAS in the kidney. Matsusaka et al. investigated the role of the local RAS in renal development and function by producing mice with genetic deletion of angiotensinogen synthesis in the kidney. In contrast to the morphological and functional consequences of whole body or liver specific deletion of angiotensinogen gene expression, deletion of angiotensinogen production in the