Pancreatic renin-angiotensin system: a novel target for the potential treatment of pancreatic diseases?

The hormonal renin-angiotensin system (RAS) has important physiological functions, which are related directly and indirectly to the regulation of blood pressure, fluid and electrolyte balance [1]. The potent vasoconstrictor action of angiotensin II (Ang II) originates from hepatic precursor angiotensinogen, where it is cleaved by the renal enzyme renin in the circulating blood. The product, Ang I, is subsequently hydrolyzed to Ang II by the pulmonary angiotensin converting-enzyme (ACE). However, alternate enzymes to renin and ACE can generate different RAS products called angiotensins in addition to Ang II including Ang III, Ang IV and Ang (1-7). The resultant angiotensins exert their physiological actions via their specific receptors, namely AT 1 , AT 2 , AT 4 , and AT 7 respectively. In this regard, a homologue of ACE, termed ACE2, has recently been identified and shown to be an essential regulator of heart function [2]. Unlike ACE, ACE2 acts as a carboxypeptidase on Ang II yielding Ang (1-7). Ang II can be also converted into Ang III and Ang IV by aminopeptidases. Ang IV binds at the AT 4 receptor which affects learning and memory and cognitive functions [3]. Recently, it has been demonstrated that many tissues/organs exhibit their own RAS products and activities. Such an intrinsic RAS can cater to specific local functions of their respective tissues/organs which are different from, complimentary or counteracting to the hormonal RAS, frequently in a paracrine and/or autocrine action [4]. They include cell proliferation, anti-proliferation, apoptosis, superoxide generation, and vasoconstriction as well as vasodilatation. These actions, as it has recently been found in the literature, extend beyond the nervous and cardiovascular systems and include such diverse targets as the pancreas [5]. In the pancreas, previous studies have made an incremental but significant advance in the knowledge of the expression, localization, regulation and potential function of a pancreatic RAS. It has been demonstrated that major components of such a local pancreatic RAS are responsive to a number of physiological stimuli and clinical conditions [6]. The available data indicate that a pancreatic RAS would be important for regulating the exocrine and endocrine functions such as acinar digestive enzyme secretion, islet hormonal secretion and ductal anion secretion. Aberrations from a normal regulation of a pancreatic RAS may be of clinical relevance in some pancreatic diseases. In this regard, a collection of up-to-date publications which specifically address the potential role of the pancreatic RAS and its clinical …