- (2003) Volume 4, Issue 2
| Po Sing Leung Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong. Shatin, Hong Kong |
| Corresponding Author: Po Sing Leung Department of Physiology Faculty of Medicine The Chinese University of Hong Kong Shatin, New Territories Hong Kong Phone +852-2609.6978 Fax +852-2603.5022 E-mail psleung@cuhk.edu.hk |
Keywords |
| Cystic Fibrosis; Diabetes Mellitus; Islets of Langerhans Transplantation; Pancreas; Pancreatitis; Renin-Angiotensin System |
Abbreviations |
| ACE: angiotensin convertingenzyme; Ang: angiotensin; AT: angiotensin receptor type; PET: pancreatic endocrine tumor; RAS: renin-angiotensin system |
| 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 AT1, AT2, AT4, and AT7 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 AT4 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 implications was available in a roundtable discussion published in JOP. J Pancreas [7]. |
| In terms of an exocrine pancreas, it has previously been shown that acute pancreatitis could markedly upregulate the expression of RAS components thus implicating its clinical relevance to pancreatitis [8]. In this respect, recent findings have further demonstrated that the administration of RAS inhibitors, such as antagonist for Ang II receptors in ceruleininduced pancreatitis, could be protective against the severity of pancreatic injury. This implies that activation of a pancreatic RAS in acute pancreatitis plays a role in pancreatic tissue injury [9]. Interestingly, the administration of RAS inhibitors could ameliorate oxidative stress and tissue injury in cerulein-induced pancreatitis [10]. Such a protective effect may open up a new strategy in the treatment of pancreatitis by virtue of using Ang II receptor antagonists rather than antioxidant therapy. Interestingly, a recent study has demonstrated that Ang II can activate calcium-mediated chloride channels in both cystic fibrosis and pancreatic epithelial cells, indicating a role for pancreatic RAS in regulating pancreatic ductal secretion and its clinical relevance to cystic fibrosis [11]. |
| The endocrine role of pancreatic RAS in the regulation of islet blood flow thus affecting insulin secretion by pancreatic islet cells has previously been reported [12]. In this respect, our preliminary data have demonstrated that major RAS components were expressed in endogenous pancreatic islet cells and the AT1 receptor was specifically localized to insulinsecreting beta cells. In addition, AT1 receptor was subjected to upregulation in transplanted islets, indicating the significance of islet RAS in islet hormonal secretion through graft function [13]. Interestingly, Ang II was observed to decrease, in a dose-dependent manner, the insulin release by isolated pancreatic islet cells, which was inhibitable by losartan, an AT1 receptor antagonist (unpublished data). These data indicate that a pancreatic RAS may play a role in regulating islet hormonal secretion, which should be clinically relevant to diabetes mellitus. On the other hand, a recent study has demonstrated that a local pancreatic RAS was subjected to regulation by pancreatic endocrine tumour (PET) and the significance of the changes may have implications in patients with PET [14]. Of great interest in this context are recent findings that the AT4 receptor is the enzyme insulin-regulated aminopeptidase, suggesting its potential role in glucose uptake [15]. Whether or not the AT4 receptor is present in the pancreas and its potential role in diabetes mellitus need intensive investigation. |
| As far as the pancreas is concerned, the most significant disorders of the exocrine pancreas are acute and chronic pancreatitis, adenocarcinoma and cystic fibrosis while the main disorders of the endocrine pancreas are diabetes mellitus and islet cell tumors. The immediate question is whether a future target for a pancreatic RAS, using specific RAS blockers, could provide a novel pathway for the potential treatments of some exocrine and endocrine pancreatic diseases. Alternatively, the development of the potential use of some agents from natural sources such as herbal medicines could be promising in manipulating the pancreatic RAS. To this end, considerable bricks should be added to this fascinating building of a pancreatic RAS. |
Acknowledgements |
| The work in this paper was fully supported by a grant from the Research Grants Council of Hong Kong (Project no. CUHK 4075/00M & 4116/01M) |
