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Journal of the Pancreas Open Access

  • ISSN: 1590-8577
  • Journal h-index: 82
  • Journal CiteScore: 35.06
  • Journal Impact Factor: 24.75
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  • Average article processing time (30-45 days) Less than 5 volumes 30 days
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- (2001) Volume 2, Issue 1

Local Renin-Angiotensin System in the Pancreas: The Significance of Changes by Chronic Hypoxia and Acute Pancreatitis

Po Sing Leung
 Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong. Shatin, N.T., Hong Kong
Corresponding Author
Po Sing Leung
Department of Physiology
Faculty of Medicine
The Chinese University of Hong Kong
Shatin, N.T.
Hong Kong
Phone +852-2609.6879
Fax +852-2603.5022
E-mail psleung@cuhk.edu.hk
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Abstract

The circulating renin-angiotensin system (RAS) plays an important role in the maintenance of blood pressure and fluid homeostasis. Recently, there has been a shift of emphasis from the circulating RAS to the local RAS in the regulation of individual tissue functions via a paracrine and/or autocrine mechanism. In fact, a local RAS has been proposed to be present in an array of tissues including the brain, heart, kidney and gonads. Our previous studies have provided solid evidence that several key elements of the RAS, notably angiotensinogen and renin, are present in the rat pancreas. The data support the existence of an intrinsic RAS in the pancreas and this local RAS may be important for the exocrine/endocrine functions of the pancreas. Interestingly, such a pancreatic RAS has been demonstrated to be markedly activated by experimental rat models of chronic hypoxia and acute pancreatitis. The activation of the pancreatic RAS by chronic hypoxia and experimental pancreatitis could play a role in the physiology and pathophysiology of the pancreas. The significant changes of pancreatic RAS may have clinical relevance to acute pancreatitis and hypoxia-induced injury in the pancreas.

Keywords
Angiotensinogen; Anoxia; Pancreas; Pancreatitis; Renin-Angiotensin System

Abbreviations
AT1: angiotensin II receptor type 1; AT2: angiotensin II receptor type 2; RNS: reactive nitrogen species; ROS: reactive oxygen species

INTRODUCTION
The circulating renin-angiotensin system (RAS) plays a crucial endocrine role in the physiology of blood pressure and electrolyte balance [1]. Recently, there has been a shift of emphasis from an endocrine role of RAS to an autocrine/paracrine control of tissue functions which is becoming critical to the understanding of regulatory mechanisms in individual tissues. The presence of key RAS component genes particularly at the level of angiotensinogen and renin which, in turn, are indispensable for the existence of a local RAS in a variety of tissues, has been previously documented [2, 3, 4]. The existence of locally formed RAS components in multiple tissues including the brain, heart, kidney and gonads has led to the assumption that angiotensin II may act as a local hormone. It may either potentiate the systemic functions or have entirely separate activities which meet the tissue needs [5, 6]. In the reproductive tissues, a local RAS has been proposed and it may be important in the regulation of various reproductive functions [7, 8, 9]. Such a local RAS has been recently reported in the rat epididymis [10, 11] with a paracrine or autocrine control of epididymal and sperm functions [12]. Interestingly, the gene expression of the epididymal RAS was regulated developmentally [13] as well as by testicular-hormones [14].

Pancreatic RAS and its Potential Functions
In the pancreas, the notion of a local RAS and its potential role have been previously reported in the dog [15, 16], the rat [17] and in humans [18]. The data suggested that the pancreatic RAS may play an autocrine/paracrine role in the regulation of the endocrine/exocrine functions of the pancreas. The RAS has recently been shown to regulate islet blood flow and thus the endocrine function of insulin secretion in the rat pancreas [19]. The effect of the RAS on oxygen tension and blood flow in transplanted pancreatic islets were also demonstrated [20]. In addition, the RAS was highly activated in shock states and was suggested to be involved in the pathophysiology of the markedly deteriorated splanchnic circulation including the pancreas [21].
The existence of a pancreatic RAS and its potential role in the regulation of exocrine function have been studied in our laboratory. Our previous studies showed that angiotensin II receptor subtypes, namely AT1 and AT2 [22] and angiotensin II [23] were predominantly localized in the epithelia and endothelia of the pancreatic ducts and blood vessels respectively of the rodent pancreas. The existence of such a pancreatic RAS has been further consolidated based on the expression and localization of key RAS component genes, which were localized coincidentally in the endothelia of the vasculature and epithelia of pancreatic ducts [24]. All these data suggest that a pancreatic RAS may play a paracrine/autocrine role in the regulation of pancreatic microcirculation and ductal anion secretion. In fact, our recent results have demonstrated that such a local RAS could mediate pancreatic blood flow (data not yet published) and ductal anion secretion [25] in the rat pancreas.

Activation of Pancreatic RAS by Chronic Hypoxia and by Acute Pancreatitis
The regulation of the major RAS component genes is controlled by an array of factors such as hormones, ions and stress [6]. One of these factors, namely hypoxic stress has been shown to result in the activation of the local RAS in tissues including the kidney [26], lung [27] and heart [28]. These data suggest that activation of the RAS by chronic hypoxia should be important for the physiological and pathophysiological changes of these tissue functions. It has been thought that prolonged hypoxia causes decreased blood flow to the tissues, which may in turn lead to tissue inflammation and injury. For example, alcohol was believed to induce hypoxia in the pancreas which could, in turn, provide a mechanism for pancreatic injury such as pancreatitis [29]. It has also been shown that angiotensin II-mediated selective pancreatic vasoconstriction results in significant pancreatic ischemia/hypoxia during exposure to stress such as cardiogenic shock [30]. In fact, chronic hypoxia has been known to cause some forms of tissue injury such as inflammatory synovitis [31]. However the influence of hypoxia on the pancreatic RAS and its pathophysiological significance are far less clear. Interestingly, our recent study demonstrated that the pancreatic RAS was subject to the activation by chronic hypoxia, notably at the levels of its locally formed angiotensinogen, AT1b and AT2 receptor subtypes [32]. Such activation of pancreatic RAS by chronic hypoxia could play a role leading to hypoxiainduced pancreatic injury such as acute pancreatitis.
Although the etiology of acute pancreatitis is believed to be multifactorial, the activation of proteolytic enzymes, lipase, kinins and other active peptides may be some of the crucial mediators responsible for alterations of RAS expression [33, 34]. In fact, previous studies have shown that the activity of the plasma RAS significantly increased in acute pancreatitis [35, 36]. In addition, the severity of acute pancreatitis is correlatively associated with the impairment of pancreatic microcirculation [37]. Nevertheless, the association between acute pancreatitis and the RAS, with particular reference to a local RAS in the pancreas, has received little attention. Interestingly, our recent study established this linkage by showing that acute pancreatitis dramatically induces the expression of the pancreatic RAS components, particularly the angiotensinogen, and AT1a and AT2 receptor subtypes [38]. Such activation could play a role in the pathophysiology of acute pancreatitis.

The Role of RAS in the Regulation of Free Radicals and Apoptosis, and its Implications to the Pancreatic Injury
The data prompt us to speculate that the activation of the pancreatic RAS by chronic hypoxia and by acute pancreatitis could have a prominent role in the physiology and possible pathophysiology of the pancreas. Inflammation/injury of the pancreas can be initiated by several means, including excess alcohol intake, probably involving an alcoholinduced hypoxia mechanism [29], pancreatic duct obstruction resulting from a migrating gallstone, pancreatic ischemia/hypoxia [30] or by a vast array of mediators [39, 40]. One significant feature of many of these mediators, however, is that reactive oxygen species (ROS) and reactive nitrogen species (RNS) may be involved in their mechanism of action and free radicals are known to induce apoptotic cell death in various cell types such as endothelial and smooth muscle cells [41]. In the pancreas, free radicals were also previously reported to be involved in the pathophysiology of acute pancreatitis [42].
The RAS has recently been shown to play a role in mediating the ROS and RNS species in various cell types such as the vascular cells [43, 44]. Moreover, RAS, in particular with the AT2 receptor subtype, was previously addressed in the regulation of vascular injury [45] and in the control of apoptosis [46]. Although the physiological role of AT2 receptor subtype in many tissues, especially in the pancreas remains unsettled, the upregulation of this receptor subtype is associated with apoptotic cell death and pathogenesis in tissues including the heart [47, 48], lung [49] and ovary [50]. Interestingly, the ROS were reported to be synthesized by endothelial and vascular smooth muscle cells using NADPH oxidase and, in turn, angiotensin II could stimulate enhanced ROS production via the increased activity of NADPH oxidase [51]. The role of the RAS in the regulation of the ROS via increased activity of NADPH oxidase and the role of vascular apoptotic cell death in the pathogenesis of atherosclerosis have recently been demonstrated [52, 53]. Nevertheless, the significance of activation of the pancreatic RAS and its association with the regulation of free radicals and apoptosis in the pancreas has yet to be investigated.

Conclusion
Our recent studies, which focused on the pancreas, have provided solid evidence for the presence of a local RAS in the pancreas, which may be important for the regulation of the exocrine/endocrine functions of the pancreas. Such a pancreatic RAS was subject to activation by chronic hypoxia and acute pancreatitis. The significance of the activation of the pancreatic RAS by chronic hypoxia and acute pancreatitis, and its role in the induction of free radicals and apoptotic cell death in the pancreas may have physiological and pathophysiological relevance to the pancreas.

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