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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Exocrine pancreatic RAS
  5. Endocrine pancreatic RAS
  6. Conclusion
  7. Acknowledgements
  8. References

Aliment Pharmacol Ther 2011; 34: 840–852

Summary

Background  In addition to the circulating (endocrine) renin–angiotensin system (RAS), local renin–angiotensin systems are now known to exist in diverse cells and tissues. Amongst these, pancreatic renin–angiotensin systems have recently been identified and may play roles in the physiological regulation of pancreatic function, as well as being implicated in the pathogenesis of pancreatic diseases including diabetes, pancreatitis and pancreatic cancer.

Aim  To review and summarise current knowledge of pancreatic renin–angiotensin systems.

Methods  We performed an extensive PubMed, Medline and online review of all relevant literature.

Results  Pancreatic RAS appear to play various roles in the regulation of pancreatic physiology and pathophysiology. Ang II may play a role in the development of pancreatic ductal adenocarcinoma, via stimulation of angiogenesis and prevention of chemotherapy toxicity, as well as in the initiation and propagation of acute pancreatitis (AP); whereas, RAS antagonism is capable of preventing new-onset diabetes and improving glycaemic control in diabetic patients. Current evidence for the roles of pancreatic RAS is largely based upon cell and animal models, whilst definitive evidence from human studies remains lacking.

Conclusions  The therapeutic potential for RAS antagonism, using cheap and widely available agents, and may be untapped and such roles are worthy of active investigation in diverse pancreatic disease states.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Exocrine pancreatic RAS
  5. Endocrine pancreatic RAS
  6. Conclusion
  7. Acknowledgements
  8. References

Whilst a great deal is known of both physiological exocrine and endocrine pancreatic function, significantly less is known of their orchestration and pathophysiology. Increasing evidence suggests that local pancreatic renin–angiotensin systems, in combination with other crucial peptides and molecules, may be important regulators of both.

The circulating RAS

The classical, circulating (endocrine or systemic) renin–angiotensin system (RAS) was originally described as a key regulator of intravascular homoeostasis, controlling extracellular fluid volume, blood pressure and absorption of electrolytes.1, 2 In response to decreased afferent arteriolar pressure, decreased filtered sodium load (from low plasma sodium concentrations or decreased glomerular filtration) or sympathetic nervous stimulation, the renal juxtaglomerular apparatus releases renin.3 This aspartyl protease cleaves a leucine-leucine peptide bond in the hepatically derived α2 globulin angiotensinogen4 to yield the non-pressor decapaptide angiotensin I (ang I). Angiotensin-converting-enzyme (ACE) is a peptidyl dipeptidase which hydrolyses ang I to yield the pressor octapeptide angiotensin II (ang II),5 whose effects are mediated through two specific human receptors (AT1R and AT2R).6 A third receptor (type 4 [AT4R]) also exists, which is more sensitive to the degradation product angiotensin IV. The roles of the AT2 and AT4 receptors in the endocrine RAS are less well defined7, 8 than that of the AT1R which, when stimulated by ang II, mediates a hypertensive response through primary vasoconstriction and the release of aldosterone, thus promoting sodium and water resorption from the distal convoluted tubule and collecting ducts.8 ACE is also a potent kininase, reducing the activity of bradykinin at its BK1 and BK2 receptors.9–12 Increasing ACE activity therefore drives hypertensive responses (increased AT1R receptor activation) and diminishes hypotensive responses (reduced vasodilation via BK2 receptor activation) (see Figure 1). In these ways, RAS plays an important role in the regulation of human blood pressure and salt and water balance.13

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Figure 1.  Physiological effects of the circulating renin–angiotensin system.

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ACE2 & alternative ang-processing enzymes

ACE 2, a homologue of ACE with 42% sequence homology,14 is an 805-amino acid zinc metalloprotease, which is now increasingly recognised as being of importance. ACE 2 functions as a carboxypeptidase when acting upon ang I and II15 and exists in both membrane-bound and soluble forms14; however, unlike ACE, it neither hydrolyses nor is inhibited by bradykinin.16 ACE 2 is capable of cleaving the terminal leucine from ang I to generate ang (1-9),14 but has much greater (approximately 400-fold) affinity for ang II.17 ACE 2 also cleaves the terminal phenylalanine residue from ang II to synthesise ang (1-7).16 ACE2 has been suggested to act either independently or in conjunction with ACE in regulation of the local RAS and may therefore be important in novel pathways of angiotensin metabolism.

Ang (1-7), the primary product of ACE2 action on ang II, acts via the Mas receptor,18 which, in contrast to the vasoconstrictor and pro-inflammatory effects mediated via ang II action on the AT1 receptor, produces vasodilation via activation of bradykinin and nitric oxide,19 prostaglandin release20 and norepinephrine inhibition.21 ACE2 therefore negatively regulates the RAS and is likely to act as an endogenous ACE inhibitor through alterations in formation of angiotensin II and angiotensin (1-7); thereby counter-balancing ACE action.

A variety of alternate ang I-processing enzymes also exist, such as chymase, chymotrypsin, tonin, aminopeptidase A, B and N, prolylendopeptidase, and neutral endopeptidase, which derive a range of other less biologically active compounds (Ang II (1-7), Ang III and Ang IV).

A local RAS

Following initial observations, in the 1990s, that many peripheral tissues were capable of generating RAS components, the existence of a local (tissue) RAS has become increasingly recognised in tissues as diverse as the heart,22 kidney,23 vasculature,24 adipose tissue,25 liver,26 nervous tissue/brain,23 adrenals,27 gonads/reproductive system,28 the gastrointestinal system29 and the pancreas.24, 30 Similarly, ACE2 has now been identified in human heart, kidneys, testes14 and small and large intestine,16 as well as in rodent lung, adipose tissue,31 liver,26 brain32 and pancreas33 and is thought to be ubiquitously expressed.

Local RAS may mediate intracellular communication between different cell types (a paracrine role), cells of the same type (autocrine role), or signal within a cell (intracrine role). Such systems may be complete, or ‘depleted’– being dependent for their function on the uptake of some critical RAS components from the circulation34–36– and may have a myriad of roles, including the regulation of cell growth, differentiation, apoptosis and proliferation; metabolism and generation of reactive oxygen species and free radicals; tissue inflammation and fibrosis; local haemodynamics; and hormonal secretion and reproduction.37–40

A local pancreatic RAS

The existence of pancreatic tissue RAS has now been confirmed in a variety of species including mice, rats, dogs and humans.24 Expression of ang II, ang III and ang II (1-7), at levels higher than that in circulating blood41 and angiotensinogen protein and mRNA have been identified in the canine pancreas.41 Immunohistochemical studies have also shown that ang II and its AT1 and AT2 receptors are expressed on the epithelia of rat pancreatic ducts, endothelia of pancreatic blood vessels and in acinar cells.42 Ang II specific-binding sites and expression of AT1 and AT2 have also been demonstrated in the exocrine rat pancreas,43 and at the molecular level in rat endothelial, acinar and ductal cells.39 mRNA levels of AT1 and AT2 receptors and angiotensinogen, have also been discovered and quantified in isolated rat pancreatic acinar cells, via semi quantitative reverse transcriptase polymerase chain reaction (PCR).44

Ang II-specific binding-sites have similarly been identified in the endocrine rat pancreas43 and endocrine AT1 and AT2 receptor expression have been confirmed at the molecular level on rat islet cell membranes.39 Reverse transcriptase PCR has also been utilised to show the presence of ang II receptors in rat pancreatic stellate cells.45

Similar findings have been made in mice42 and specifically in mouse MIN6 cells (a highly differentiated and glucose-responsive murine β cell line),46 and ACE2 has also been confirmed in mouse pancreata.33 Canine pancreatic Ang (1-7)41 and rat pancreatic ACE2 protein and mRNA47 have also been confirmed.

Thus, both canines and rodents appear to have a pancreatic RAS and mounting evidence now confirms the presence of a human pancreatic RAS. Immunocytochemical approaches have localised expression of AT1R and (pro)renin to the beta cells of the islets of langerhans and also to endothelial cells of the pancreatic vasculature.48 However, non-isotopic in situ hybridisation has shown that localisation of (pro)renin mRNA transcription may be confined to connective tissue surrounding blood vessels and reticular fibres within the islets, whereas immuno-staining revealed that the protein itself was largely confined to the cells themselves, suggesting that renin may be released from sites of synthesis and taken up by cellular sites of action.48 Expression of angiotensinogen and AT1Rs has been demonstrated in human pancreatic islets and ducts.49 Single-cell reverse transcriptase-PCR and western blotting have shown expression of mRNA and protein for AT1Rs and mRNA for both angiotensinogen and ACE in human islets.46 The expression of angiotensinogen, ACE and AT1R mRNAs in isolated human islets has been confirmed by PCR50; and immunocytochemistry and in situ hybridisation have also been utilised to reveal that the AT1R is expressed in human pancreatic stellate cells (HPSC).51

Exocrine pancreatic RAS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Exocrine pancreatic RAS
  5. Endocrine pancreatic RAS
  6. Conclusion
  7. Acknowledgements
  8. References

Renin–angiotensin system in pancreatic acinar cells

Expression of AT1 and AT2 receptors, ang II and other components have been demonstrated in primary exocrine pancreas preparations from mouse, rat and human, as well as in cell lines such as the rat AR42J (pancreatic acinar tumour cell line with exocrine and neuroendocrine properties) cells. The mechanism of stimulus-secretion coupling of acinar cells, and in particular the fundamental role of intracellular Ca2+ has been extensively studied52: the main agonists, acetylcholine (Ach) and cholecystokinin (CCK), trigger acinar cytosolic Ca2+ signals by activating either phospholipase C-inositol 1,4,5 trisphosphate (IP3) or cyclic-ADP-ribose-NAADP mediated Ca2+ release from the endoplasmic reticulum or intracellular acidic Ca2+ stores, respectively. The AT1R is most frequently coupled to Gq/11-mediated inositol phosphate/Ca2+ signalling,53 a pathway that increases amylase secretion in AR42J cells following activation by ang II.54, 55 Similarly, ang II action at the AT1R leads to a dose-dependent release of acinar digestive enzymes (amylase and lipase) in isolated rat pancreatic acinar cells44 (see Figure 2).

image

Figure 2.  Local physiology of the exocrine pancreatic renin–angiotensin system.

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Local ACE expression also plays a fundamental pro-inflammatory role in diverse tissues including brain,56 kidney,57, 58 lung,59 vasculature,60–62 heart63 and eye.64 This is most likely to occur through an ang II–NF-κβ65–67 pathway and involves activation of mediators such as interleukins 668, 69 and 8,67 and MCP-1,65, 70 possibly through a mitogen-activated protein kinase (MAPK) signalling mechanism.71 Increasing evidence suggests that the pancreatic RAS may similarly play a role in the pathophysiology of pancreatic inflammation and injury. Although acute pancreatic inflammation has diverse triggers, the same common pathways lead to pancreatic injury. Novel, basic research strategies suggest that various inflammatory and vasoactive molecules, such as ang II, substance P and cyclooxygenase 2 may have crucial roles in the aetiology of the disease process,72 via premature activation of pancreatic proteolytic proenzymes, such as trypsinogen,37, 73 and subsequent initiation of a cycle of gland autodigestion, oedema, cell necrosis, haemorrhage and severe inflammation.

First, ACE inhibition increases pancreatic microvascular permeability and nitric oxide synthase activity in fructose-fed rats.74 Consistent with this, ACE inhibition can cause AP, and use of such agents is associated with a modest dose-dependent increase in the risk of AP in the first 6 months of use.75–78 Thus, in the normal pancreas, low ACE activity may trigger pancreatitis. However, once triggered by other stimuli or established, it appears to be elevated RAS activity that may prove harmful.

Progressive tissue hypoxia occurs in pancreatitis as a result of microcirculatory vasoconstriction and stasis,79 and can also result from alcohol exposure (one of the leading causes of pancreatitis in the west).80 In addition, tissue hypoxia itself can decrease regional pancreatic blood flow, and enhance tissue inflammation and injury.81 Such hypoxia is known to stimulate RAS expression in tissues such as lung,82 kidney,83 carotid body84 epididymis85 and heart.86 This also seems true in the pancreas, where chronic hypoxia up-regulates mRNA and protein expression of angiotensinogen, AT1R and AT2R in rodents, effects postulated to worsen microcirculatory flow.87

Activated plasma renin activity is elevated in AP, as compared to other syndromes of acute abdominal pain,88, 89 although ACE levels have been demonstrated not to change in acute or chronic pancreatitis, or pancreatic adenocarcinoma.90 However, the fact that a multitude of ang-processing and -synthesising enzymes are now known to exist, means that ACE levels may not represent true, overall RAS activity. Greenstein et al.88 suggested that increased renin activity may be due to decreased circulating plasma volume seen in AP, or possible activation by proteolytic enzymes triggered in AP. However, of perhaps greater significance is the increased expression of pancreatic RAS which is associated with pancreatitis. In experimentally induced pancreatitis in rats, western blotting, semi-quantitative reverse transcriptase-PCR and immunohistochemical approaches demonstrate increased expression of angiotensinogen and AT2Rs.91 These observations have been confirmed in intraperitoneal caerulein (a decapeptide analogue of the potent pancreatic secratogogue CCK) – mediated AP, and extended to show additional elevation in AT1R expression.92 Such up-regulation may be pathogenic: ang II action at the AT1R causes pancreatic acinar cell apoptosis.93 Ang II, via AT1R activation, also increases the expression of monocyte chemoattractant protein-1 (MCP-1), a chemokine important in the recruitment of mononuclear cells into the pancreatic islets, in the rat insulin-secreting (RINm5) β cell-line. It also activates the MCP-1 promoter.70 In a rat model of obstructive pancreatitis, AT1R activation has a pro-inflammatory effect which drives the development of pancreatitis, perhaps through NADPH oxidase-dependant NF-κβ activation72, 94 (see Figure 3). ACE2 may counterbalance these actions by attenuating fibrosis and inflammation via inhibition of TGF95 and macrophage migration inhibitory factor.96

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Figure 3.  Potential pathogenic mechanisms of the exocrine pancreatic renin–angiotensin system.

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More directly, ACE inhibition also attenuates tissue injury and fibrosis in chronic pancreatitis.97, 98 Serum and pancreatic levels of matrix metalloproteinase-9 (MMP-9), which disrupts basement membranes and increases vascular permeability, are also reduced.98 At least some of this effect is mediated through altered ang II activity at the AT1R (but not AT2R).92, 99 Indeed, caerulein-induced pancreatitis is associated with increases in pancreatic and pulmonary myeloperoxidase (an enzyme located predominantly in neutrophil granulocytes and implicated in the generation of reactive oxygen species), and elevated pulmonary microvascular permeability is prevented by AT1R antagonism.100

Pathological increases in cytosolic and mitochondrial [Ca2+] have been shown to trigger cell death of pancreatic acinar cells, primarily through necrotic pathways, common to mitochondria-mediated pathologies.101 Furthermore, the primary mechanism underlying alcohol- and fatty acid- mediated cytotoxicity in the acinar cell (seen in pancreatitis) involves specific Ca2+ release from type 2 and 3 IP3 receptors; whereas, their genetic ablation or inhibition by calmodulin can significantly inhibit AP.102–104

A polymorphism of the human ACE gene has been identified in which the absence (Deletion, D allele) rather than the presence (Insertion, I allele) of a 287 base pair fragment is associated with higher circulating,105 tissue (e.g. myocardium),106 and inflammatory cell (e.g. monocytes)107 ACE activity; potentially helping to explain the substantial variation in inflammatory response seen in AP when separate individuals are exposed to similar inflammatory triggers. Studies investigating the influence of such ACE polymorphisms have to date revealed no significant association with development or severity in acute,108 chronic,109–111 familial110 or tropical calcific pancreatitis.112 However, studies to date have been limited in number and sample size, as well as often being composed of heterogeneous patient cohorts.

Thus, local ang II generation is implicated in the initiation and propagation of AP, pancreatic cell injury, and its pulmonary sequelae via a number of possible mechanisms including generation of reactive oxygen species and various other pro-inflammatory and vasoactive peptides such as MMP-9, MCP-1, NADPH, NF-κβ, TGF and Smad.

Renin–angiostenin system in pancreatic ductal cells

Ang II has been shown to have effects upon both current and secretion in secretory epithelia of the trachea, jejunum and colon.113, 114 In isolated canine pancreatic ductal cells, calcium channel activation via the AT1R was shown to be necessary for bicarbonate secretion,115 whilst pharmacological ACE inhibition reduced secretin-induced bicarbonate output in conscious dogs.116 In cystic fibrotic human pancreatic duct cell lines (CFPAC-1), ang II dose dependently increased the current and promoted electrogenic chloride ion secretion, an effect which was abolished by selective AT1R antagonism.117 Furthermore, activation of the AT1R was shown to be by cAMP and Ca2+-dependant responses mediated by the Gi-coupled PLC pathway.118, 119 Such data suggest that ACE-generated ang II, acting via the AT1R, may regulate pancreatic ductal bicarbonate and chloride secretion.

Renin–angiotensin system activity may also be crucial in the development of pancreatic ductal adenocarcinoma (PDAC). Investigation of various PDAC cell lines (SW1990, PaTu8988s, HPAF-II, AsPC-1 and PANC-1), utilising various techniques including RT-PCR, has shown that mRNA and protein for both the AT1 receptor, which is present on the plasma membrane and within the cytoplasm, is expressed in all cell lines and at much higher levels than that found within human colon cancer cell lines.120–123 Furthermore, the growth of such PDAC cell-lines can be significantly suppressed by RAS antagonist treatment, in a dose-dependent fashion.124 Tissue ang II levels have also been shown to be significantly elevated in resected human pancreatic cancer tissue, as compared to similarly resected tissues from normal pancreas, colon cancer or hepatocellular carcinoma.122, 123 However, no significant differences in tissue ACE activity were found between the various tissues in this investigation, potentially providing indirect, in vivo evidence of ACE-independent ang-II generating and -processing systems within PDAC tissues.

In fitting with its RAS counter-balancing actions, ELISA and western blot analyses have shown that ACE2 levels are decreased in PDAC cell-lines in which high levels of ang II are expressed, where further reduction of ACE2 via RNA interference promotes the proliferation of cancerous cells.125

Pancreatic cell-line studies (HPAF-II, AsPC-1 and Panc-1) demonstrate that ang II may act within PDAC cells to stimulate cancer cell growth via MAPK activation, as well as significantly reducing cisplatin-induced apoptosis through NF-κβ activation and the subsequent generation of anti-apoptotic molecules, including Bcl-XL and survivin.120 Ang II may also induce the crucial pro-angiogenic component of PDAC, vascular endothelial growth factor (VEGF), whose high expression levels correlate closely with poor outcome in pancreatic cancer. Anandandesan et al.126 showed that high levels of ang II colocalise with VEGF in invasive PDAC, and that ang II induces VEGF expression in pancreatic cancer cell-lines; whereas, AT1 receptor antagonists significantly inhibit synthesis of VEGF mRNA and protein, possibly via a MAPK signalling mechanism and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2). Furthermore, immunohistochemical analysis demonstrated increased expression of AT1 receptor in most ductal cells undergoing metaplasia, suggesting its involvement in tumour angiogenesis and subsequent progression. Arafat et al.127 similarly analysed ACE, AT1 receptor and VEGF in invasive human PDAC using real-time PCR, western blotting and immunohistochemistry to find that ACE and AT1 receptor levels were significantly up-regulated in 75% of neoplastic tissues and VEGF was significantly higher in tissue expressing high levels of AT1 receptor and ACE. Furthermore, ACE, AT1R and VEGF colocalised within malignant ducts and stromal cells, and ang II addition significantly enhanced VEGF mRNA and protein production, an effect that was prevented through pre-incubation with losartan or captopril.

Indeed, ACE-inhibitors and AT1 receptor antagonists have been shown to have profound cytostatic properties on a variety of in vitro cells and tissues128 and these effects may hold true for PDAC. Treatment of hamster pancreatic ductal cancer cells with ACE inhibitors captopril and CGS 13945 (10(-8) to 10(-2)M), which lack both ACE and renin activity, has shown that both inhibitors are capable of producing a dose-dependent reduction in cancer cell proliferation within 24 h, although neither obviously affected cell viability or cell cycle.129 Slot blot analysis demonstrated that both agents increased K-ras expression by a factor of 2; captopril also lowered proliferation-associated cell nuclear antigen (PCNA) by 40% and CGS 13945 reduced PKC-beta gene expression to 30% of the control level, illustrating that the anti-mitotic action may be independent of traditional RAS and may occur through down-regulation of growth-related gene expression. It appears that such ACE-inhibitors as captopril, which contain a sulphydril or thiol radical in their moiety, are more effective in controlling the growth of neoplastic cells than those without, possibly via additional antioxidant and metalloproteinase controlling activity, even if those without a thiol residue demonstrate a stronger in vivo inhibitory effect upon ACE activity.128

Therefore, ang II may play a crucial role in the development of PDAC, via stimulation of VEGF and angiogenesis, as well as through prevention of chemotherapy toxicity; and its development may be influenced by both traditional, ACE-dependant and novel, ACE-independent pathways. Ang II has also been used as a novel intra-arterial treatment for advanced PDAC, along with traditional chemotherapy agents, such as 5-fluorouracil, methotrexate and gemcitabine, in attempts to increase blood flow to tumour tissues and decrease flow to nontumour tissues, where it has yielded promising results both in terms of patient survival and quality of life.130, 131

Renin–angiotensin system in pancreatic stellate cells

The AT1R is expressed in HPSC,51 myofibroblast-like cells found within the exocrine pancreas. They share many features with their hepatic counterparts and their activation induces proliferation, migration to sites of tissue damage, contraction, phagocytosis and synthesis of extracellular matrix components to promote tissue repair.132 Activation of HPSCs may promote pancreatic fibrosis,133 whereas stellate AT1R antagonism induces dose-dependent apoptosis, and reduces the type I collagen content of HPSCs.51 Therefore, prolonged activation of HPSCs has an increasingly appreciated role in the fibrosis associated with continued attacks of AP and in chronic pancreatitis.133 TGF-β1 is a multifunctional peptide involved in cellular proliferation, differentiation and apoptosis, and Smad molecules are transcription regulation proteins, which act as a classical signalling pathway for TGF peptides. Ang II enhances activated HPSC proliferation by activating endothelial growth factor (EGF) receptors and inhibiting autocrine TGF-β1-mediated growth inhibition via induction of Smad7 expression by PKC-dependant pathways.133

Meanwhile, in vitro exposure of rat pancreatic stellate cells to high-glucose media is associated with an increase in ang II expression, and also with increased TGF-β, connective tissue growth factor, and collagen type 4 protein expression, as well as with cell proliferation.45 Both ACE inhibition and selective AT1R antagonism effectively block these responses. Thus, the hyperglycaemia associated with pancreatitis may, through AT1R activation, aggravate it in a positive feedback loop.

Endocrine pancreatic RAS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Exocrine pancreatic RAS
  5. Endocrine pancreatic RAS
  6. Conclusion
  7. Acknowledgements
  8. References

RAS in pancreatic islets

The addition of ang II to the perfusate of isolated rat pancreata induces marked vasoconstriction in the whole pancreas, but especially diminishes islet blood flow and delays the first phase of insulin release in response to glucose.134 ACE inhibition and AT1R antagonism, meanwhile, significantly (and preferentially) increase pancreatic islet blood flow in vivo in rats, and increase insulin secretion and glucose tolerance.135, 136 Thus, local ang II may influence insulin release partly through regulation of islet blood flow. However, Ang II also causes a dose-dependent inhibition of glucose-stimulated insulin release in mouse islets, although part of this effect may be due to an AT1R-dependent decrease in proinsulin synthesis.30 In immortalised rat pancreatic cell-lines (RIN-M and RIN14-B), the AT2R is expressed in somatostatin secreting islet cells, where their activation stimulates somatostatin secretion in a dose-dependent fashion, with subsequent inhibition of insulin release137 (see Figure 4).

image

Figure 4.  Local physiology of the endocrine pancreatic renin–angiotensin system.

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Such animal data are supported by those from humans. In vivo, systemic administration of ang II suppresses both basal and pulsatile insulin secretion, independent of effects on blood pressure.138 Plasma glucose concentrations rise in parallel.138 Similarly, administration of ACE inhibitors and ang II receptor blockers is consistently associated with a marked reduction in the incidence of new-onset diabetes,139–146 independent of blood pressure-lowering effects. The finding that beta-blocker administration may even increase the risk of diabetes147, 148 indicates that it is the RAS inhibition that is crucial to the reduction in diabetes. However, type 1diabetes is also prevented and glycosylated haemoglobin levels reduced.149 How might this occur?

Islet cell angiotensinogen and AT1R expression are increased in rodent models of type 2 diabetes mellitus47, 150 and at an anatomical level, ang II may drive islet (and in particular, beta cell) destruction. Ang II elicits an inflammatory response in islets from normal mice through MCP-1 stimulation.70 Meanwhile, in non-obese diabetic mice pancreata, the pattern of ACE expression correlates well with progression of insulinitis and beta cell destruction, with ACE and MCP-1 co-localising in beta cells.70

Treatment with RAS antagonists prevents islet cell destruction, fibrosis and apoptosis in OLETF and ZDF (Otsuka Long-Evans Tokushima fatty rats and Zucker diabetic fatty rats – rat models of diabetes) rats,45 and db/db mice (a mouse model of type 2 diabetes with obesity),151 an effect partly mediated through changes in NADPH-oxidase induced oxidative stress,152 via ang II action at the AT1 receptor.153

Human studies are consistent with those from animals. Expression of angiotensinogen, ACE and AT1R is increased in islets cultured in high glucose levels and normalised when ACE-inhibitors (zofenoprilat or enalaprilat) are present in the culture medium.50 Meanwhile, ACE inhibition enhances pancreatic insulin secretion in hypertensive patients,154–156 an effect perhaps in part attributable to enhanced islet blood flow.134

Thus, pancreatic RAS activation, particularly through the AT1R, acutely decreases insulin secretion in animals and humans, at least partially due to reductions in islet blood flow and proinsulin biosynthesis. It also drives islet apoptosis and fibrosis, and may subsequently contribute to islet cell dysfunction in type 2 diabetes mellitus (see Figure 5).

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Figure 5.  Potential pathogenic mechanisms of the endocrine pancreatic renin–angiotensin system.

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Furthermore, Mas receptor knockout mice exhibit many effects consistent with type 2 diabetes and the metabolic syndrome, such as increased insulin, leptin and fat mass, dyslipidaemia, impaired glucose transporter 4 expression (GLUT 4), reduced adipocyte glucose uptake and impaired glucose tolerance and insulin sensitivity, and therefore may implicate reduced or low levels of ACE2 in the development of insulin resistance and diabetes.157 The Mas receptor and ACE 2 have also been identified in hepatocytes158, 159 and adipose tissue31 and may play a role in insulin resistance.

Ang II may also have an important role in pancreatic endocrine tumours (PETs). Expression of mRNA of human angiotensinogen, ang II, AT1 and AT2 receptors, has been assessed in PETs via semi-quantitative RT-PCR and immunohistochemistry, to demonstrate that angiotensinogen and AT2 receptor levels are increased in comparison to normal pancreas.49

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Exocrine pancreatic RAS
  5. Endocrine pancreatic RAS
  6. Conclusion
  7. Acknowledgements
  8. References

Local renin–angiotensin systems exist in diverse tissues, and have roles in the regulation of metabolism, blood flow, inflammation and healing responses. The same now seems true of the pancreas, where pancreatic RAS appear to have roles in the regulation of exocrine and endocrine physiology and pathophysiology.

Ang II may play a role in the development of PDAC, via stimulation of angiogenesis and prevention of chemotherapy toxicity, as well as in the initiation and propagation of AP, via generation of reactive oxygen species and activation of both pro-inflammatory molecules and HPSC. RAS antagonism prevents new-onset diabetes and improves glycaemic control in diabetic patients, as well as enhancing islet cell mass and morphology, insulin biosynthesis and secretion. ACE2, a novel component of the RAS may act to counter-balance the actions of ang II and ACE, but further investigation of ACE2-deleted models may lead to better understanding of disease mechanisms and potential treatments.

However, current evidence for the roles of pancreatic RAS is largely based upon cell and animal models, whilst definitive evidence from human studies remains lacking. Furthermore, the presence of counter-balancing mechanism, such as that provided by the novel ACE2 molecule and Mas receptor, as well as redundancy in intracellular signalling pathways mandate further experimentation. However, it may be that the therapeutic potential for RAS antagonism using cheap and widely available agents remains untapped and such roles are certainly worthy of active investigation in diverse pancreatic disease states.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Exocrine pancreatic RAS
  5. Endocrine pancreatic RAS
  6. Conclusion
  7. Acknowledgements
  8. References

JS, who is supported as the ‘Jason Boas HPB Fellow’ by the No Surrender Charitable Trust, drafted the manuscript. All authors have significantly contributed to, read and approved the final manuscript. All authors declare that they have no competing interests. Declaration of personal and funding interests: None.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Exocrine pancreatic RAS
  5. Endocrine pancreatic RAS
  6. Conclusion
  7. Acknowledgements
  8. References