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Pancreatic RAS

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The Renin-Angiotensin System: Current Research Progress in The Pancreas

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 690))

Abstract

Metabolic syndrome disorder is a grave health problem affecting diverse populations worldwide. Among them, type 2 diabetes mellitus (T2DM) is a particularly widespread cardiometabolic syndrome which is characterized by impaired peripheral insulin sensitivity and pancreatic β-cell function. Its prevalence is ever increasing, not only in adults, but also notably in young people. Despite ongoing efforts to generally improve people’s dietary habits and exercise-related behaviour, T2DM has become an epidemic beyond preventability in many individuals. It is also recognized that, if allowed to develop, the cardiovascular and renal sequelae of T2DM will become a major financial burden on nations’ healthcare systems. Hence, we are faced with an urgent need for measures to prevent or stall disease progression. In this regard, mechanistic insight into the regulatory pathways that may be harnessed to preserve the structure and function of pancreatic islets in affected persons represents a promising approach. Knowledge garnered from elucidating these basic mechanisms can be translated into clinical applications and offers prospects for rapid development of new therapeutic strategies to limit the health impacts of T2DM and its cardiovascular complications (Garber, 2009).

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References

  • Abuissa H, Jones PG, Marso SP, O’Keefe JH Jr. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol 46:821–826, 2005.

    Article  PubMed  CAS  Google Scholar 

  • Anandanadesan R, Gong Q, Chipitsyna G, Witkiewicz A, Yeo CJ and Arafat HA. Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling. J Gastrointest Surg 12:57–66, 2008.

    Article  PubMed  Google Scholar 

  • Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC and Wilson JS. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 43:128–133, 1998.

    Article  PubMed  CAS  Google Scholar 

  • Apte MV, Haber PS, Darby SJ, Rodgers SC, McCaughan GW, Korsten MA, Pirola RC and Wilson JS. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 44:534–541, 1999.

    Article  PubMed  CAS  Google Scholar 

  • Arafat HA, Gong Q, Chipitsyna G, Rizvi A, Saa CT and Yeo CJ. Antihypertensives as novel antineoplastics: angiotensin-I-converting enzyme inhibitors and angiotensin II type 1 receptor blockers in pancreatic ductal adenocarcinoma. J Am Coll Surg 204:996–1005, 2007.

    Article  PubMed  Google Scholar 

  • Bataller R, Gines P, Nicolas JM, Gorbig MN, Garcia-Ramallo E, Gasull X, Bosch J, Arroyo V and Rodes J. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 118:1149–1156, 2000.

    Article  PubMed  CAS  Google Scholar 

  • Bateman A, Turner S, Thomas K, McCrudden P, Fine D, Johnson P, Johnson C and Iredale J. apoptosis and proliferation of acinar and islet cells in chronic pancreatitis: evidence for differential cell loss mediating preservation of islet function. Gut 50:542–548, 2002.

    Article  PubMed  CAS  Google Scholar 

  • Campbell D and Habener J. Angiotensinogen gene is expressed and differentially regulated in multiple tissues of the rat. J Clin Invest 78:31–39, 1986.

    Article  PubMed  CAS  Google Scholar 

  • Carlsson PO, Berne C and Jansson L. Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats. Diabetologia 41:127–133, 1998.

    Article  PubMed  CAS  Google Scholar 

  • Chan H, Law S, Leung P, Fu L and Wong P. Angiotensin II receptor type I-regulated anion secretion in cystic fibrosis pancreatic duct cells. J Membr Biol 156:241–249, 1997.

    Article  PubMed  CAS  Google Scholar 

  • Chappell M, Diz D and Gallagher P. The renin-angiotensin system and the exocrine pancreas. JOP 2:33–39, 2001.

    PubMed  CAS  Google Scholar 

  • Chappell M, Jacobsen D and Tallant E. Characterization of angiotensin II receptor subtypes in pancreatic acinar AR42J cells. Peptides 16:741–747, 1995.

    Article  PubMed  CAS  Google Scholar 

  • Chappell M, Millsted A, Diz D, Brosnihan K and Ferrario C. Evidence for an intrinsic angiotensin system in the canine pancreas. J Hypertens 9:751–759, 1991.

    Article  PubMed  CAS  Google Scholar 

  • Chappell MC, Diz DI and Jacobsen DW. Pharmacological characterization of angiotensin II binding sites in the canine pancreas. Peptides 13:313–318, 1992.

    Article  PubMed  CAS  Google Scholar 

  • Chehl N, Gong Q, Chipitsyna G, Aziz T, Yeo CJ and Arafat HA. Angiotensin II Regulates the Expression of Monocyte Chemoattractant Protein-1 in Pancreatic Cancer Cells. J Gastrointest Surg 13:2189–2200, 2009.

    Article  PubMed  Google Scholar 

  • Cheng H, So S, Law S and Chan H. Angiotensin II-mediated signal transduction events in cystic fibrosis pancreatic duct cells. Biochim Biophys Acta 1449:254–260, 1999.

    Article  PubMed  CAS  Google Scholar 

  • Cheng Q, Law PK, de Gasparo M and Leung PS. Combination of the dipeptidyl peptidase IV inhibitor LAF237 [(S)-1-[(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] with the angiotensin II type 1 receptor antagonist valsartan [N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methyl]-L-valine] enhances pancreatic islet morphology and function in a mouse model of type 2 diabetes. J Pharmacol Exp Ther 327:683–691, 2008.

    Article  PubMed  CAS  Google Scholar 

  • Cheung WT, Yeung SY, Yiu AK, Ip TM, Wan DC, Luk SK and Ho WK. Characterization of a functional AT1A angiotensin receptor in pancreatoma AR4-2 J cells. Peptides 20:829–836, 1999.

    Article  PubMed  CAS  Google Scholar 

  • Chipitsyna G, Gong Q, Gray CF, Haroon Y, Kamer E, Arafat HA (2007) Induction of monocyte chemoattractant protein-1 expression by angiotensin II in the pancreatic islets and beta-cells. Endocrinology 148:2198–2208, 2007.

    Article  PubMed  CAS  Google Scholar 

  • Christophe J. Pancreatic tumoral cell line AR42J: an amphicrine model. Am J Physiol 266:G963–G971, 1994.

    PubMed  CAS  Google Scholar 

  • Chu KY, Lau T, Carlsson PO and Leung PS. Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. Diabetes 55:367–374, 2006.

    Article  PubMed  CAS  Google Scholar 

  • Chu KY and Leung PS. Angiotensin II Type 1 receptor antagonism mediates uncoupling protein 2-driven oxidative stress and ameliorates pancreatic islet beta-cell function in young Type 2 diabetic mice. Antioxid Redox Signal 9:869–878, 2007.

    Article  PubMed  CAS  Google Scholar 

  • Chu KY and Leung PS. Angiotensin II in type 2 diabetes mellitus. Curr Protein Pept Sci 10:75–84, 2009.

    Article  PubMed  CAS  Google Scholar 

  • Chu KY, Cheng Q, Chen C, Au LS, Seto SW, Tuo Y, Motin L, Kwan YW and Leung PS. Angiotensin II exerts glucose-dependent effects on Kv currents in mouse pancreatic beta-cells via angiotensin II type 2 receptors. Am J Physiol Cell Physiol 298:C313–323, 2010.

    Google Scholar 

  • Cox HM, Cuthbert AW and Munday KA. The effect of angiotensin II upon electrogenic ion transport in rat intestinal epithelia. Br J Pharmacol 90:393–401, 1987.

    Google Scholar 

  • Fink AS, Wang Y, Mendez T, Worrell RT, Eaton D, Nguyen TD and Lee SP. Angiotensin II evokes calcium-mediated signaling events in isolated dog pancreatic epithelial cells. Pancreas 25:290–295, 2002.

    Article  PubMed  Google Scholar 

  • Fujita M, Hayashi I, Yamashina S, Itoman M and Majima M. Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem Biophys Res Commun 294:441–447, 2002.

    Article  PubMed  CAS  Google Scholar 

  • Garber AJ. Perspectives in type 2 diabetes: incorporating the latest insulin analogue strategies to achieve treatment success. Diabetes Obes Metab 11(Suppl 5):III–IV, 2009.

    Google Scholar 

  • Githens S. The pancreatic duct cell: proliferative capabilities, specific characteristics, metaplasia, isolation, and culture. J Pediatr Gastroenterol Nutr 7:486–506, 1988.

    Article  PubMed  CAS  Google Scholar 

  • Hama K, Ohnishi H, Aoki H, Kita H, Yamamoto H, Osawa H, Sato K, Tamada K, Mashima H, Yasuda H and Sugano K. Angiotensin II promotes the proliferation of activated pancreatic stellate cells by Smad7 induction through a protein kinase C pathway. Biochem Biophys Res Commun 340:742–750, 2006.

    Article  PubMed  CAS  Google Scholar 

  • Hama K, Ohnishi H, Yasuda H, Ueda N, Mashima H, Satoh Y, Hanatsuka K, Kita H, Ohashi A, Tamada K and Sugano K. Angiotensin II stimulates DNA synthesis of rat pancreatic stellate cells by activating ERK through EGF receptor transactivation. Biochem Biophys Res Commun 315:905–911, 2004.

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto T, Yamada T, Yokoi T, Sano H, Ando H, Nakazawa T, Ohara H, Nomura T, Joh T and Itoh M. Apoptosis of acinar cells is involved in chronic pancreatitis in Wbn/Kob rats: role of glucocorticoids. Pancreas 21:296–304, 2000.

    Article  PubMed  CAS  Google Scholar 

  • Hirata AE, Morgan D, Oliveira-Emilio HR, Rocha MS, Carvalho CR, Curi R and Carpinelli AR. Angiotensin II induces superoxide generation via NAD(P)H oxidase activation in isolated rat pancreatic islets. Regul Pept 153:1–6, 2009.

    Article  PubMed  CAS  Google Scholar 

  • Howard-McNatt M and Fink AS. Captopril inhibits secretin-induced pancreatic bicarbonate output. J Surg Res 103:96–99, 2002.

    Article  PubMed  CAS  Google Scholar 

  • Huang Z, Jansson L and Sjoholm A. Vasoactive drugs enhance pancreatic islet blood flow, augment insulin secretion and improve glucose tolerance in female rats. Clin Sci (Lond) 112:69–76, 2007.

    Article  CAS  Google Scholar 

  • Ishidoya S, Morrissey J, McCracken R, Reyes A and Klahr S. Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int 47:1285–1294, 1995.

    Article  PubMed  CAS  Google Scholar 

  • Jonsson JR, Clouston AD, Ando Y, Kelemen LI, Horn MJ, Adamson MD, Purdie DM and Powell EE. Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 121:148–155, 2001.

    Article  PubMed  CAS  Google Scholar 

  • Kida Y, Asahina K, Inoue K, Kawada N, Yoshizato K, Wake K and Sato T. Characterization of vitamin A-storing cells in mouse fibrous kidneys using Cygb/STAP as a marker of activated stellate cells. Arch Histol Cytol 70:95–106, 2007.

    Article  PubMed  CAS  Google Scholar 

  • Ko S, Kwon H, Kim S, Moon S, Ahn Y, Song K, Son H, Cha B, Lee K, Son H, Kang S, Park C, Lee I and Yoon K. Ramipril treatment suppresses islet fibrosis in Otsuka Long–Evans Tokushima fatty rats. Biochem Biophys Res Commun 316:114–122, 2004.

    Article  PubMed  CAS  Google Scholar 

  • Ko SH, Hong OK, Kim JW, Ahn YB, Song KH, Cha BY, Son HY, Kim MJ, Jeong IK and Yoon KH. High glucose increases extracellular matrix production in pancreatic stellate cells by activating the renin-angiotensin system. J Cell Biochem 98:343–355, 2006.

    Article  PubMed  CAS  Google Scholar 

  • Korc M. Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer 2:1–8, 2003.

    Article  Google Scholar 

  • Kordes C, Sawitza I and Haussinger D. Hepatic and pancreatic stellate cells in focus. Biol Chem 390:1003–1012, 2009.

    Article  PubMed  CAS  Google Scholar 

  • Kuno A, Yamada T, Masuda K, Ogawa K, Sogawa M, Nakamura S, Nakazawa T, Ohara H, Nomura T, Joh T, Shirai T and Itoh M. Angiotensin-converting enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats. Gastroenterology 124:1010–1019, 2003.

    Article  PubMed  CAS  Google Scholar 

  • Lam KY and Leung PS. Regulation and expression of a renin-angiotensin system in human pancreas and pancreatic endocrine tumours. Eur J Endocrinol 146:567–572, 2002.

    Article  PubMed  CAS  Google Scholar 

  • Lau T, Carlsson P and Leung P. Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets. Diabetologia 47:240–248, 2004.

    Article  PubMed  CAS  Google Scholar 

  • Leung PS and De Gasparo M. Novel peptides and proteins in diabetes mellitus. Curr Protein Pept Sci 10:1, 2009.

    Article  PubMed  CAS  Google Scholar 

  • Leung KK and Leung PS. Effects of hyperglycemia on angiotensin II receptor type 1 expression and insulin secretion in an INS-1E pancreatic beta-cell line. JOP 9:290–299, 2008.

    PubMed  Google Scholar 

  • Leung PS. The physiology of a local renin-angiotensin system in the pancreas. J Physiol 580:31–37, 2007.

    Article  PubMed  CAS  Google Scholar 

  • Leung PS and Carlsson PO. Pancreatic islet renin-angiotensin system: its novel roles in islet function and in diabetes. Pancreas 30:293–298, 2005.

    Article  PubMed  CAS  Google Scholar 

  • Leung PS and Chappell MC. A local pancreatic renin-angiotensin system: endocrine and endocrine roles. Int J Biochem Cell Biol 35:838–846, 2003.

    Article  PubMed  CAS  Google Scholar 

  • Leung PS, Chan WP, Wong TP and Sernia C. Expression and localization of the renin-angiotensin system in the rat pancreas. J Endocrinol 160:13–19, 1999.

    Article  PubMed  CAS  Google Scholar 

  • Leung PS, Chan HC and Wong PY. Immunohistochemical localization of angiotensin II in the mouse pancreas. Histochem J 30:21–25, 1998.

    Article  PubMed  CAS  Google Scholar 

  • Leung PS, Chan HC, Fu LX and Wong PY. Localization of angiotensin II receptor subtypes AT1 and AT2 in the pancreas of rodents. J Endocrinol 153:269–274, 1997a.

    Article  PubMed  CAS  Google Scholar 

  • Leung PS, Chan HC, Fu LX, Zhou WL and Wong PY. Angiotensin II receptors, AT1 and AT2 in the rat epididymis: immunocytochemical and electrophysiological studies. Biochim Biophys Acta 1357:65–72, 1997b.

    Article  PubMed  CAS  Google Scholar 

  • Liu WB, Wang XP, Wu K and Zhang RL. Effects of angiotensin II receptor antagonist, Losartan on the apoptosis, proliferation and migration of the human pancreatic stellate cells. World J Gastroenterol 11:6489–6494, 2005.

    PubMed  CAS  Google Scholar 

  • Masamune A, Watanabe T, Kikuta K and Shimosegawa T. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin Gastroenterol Hepatol 7:S48–S54, 2009.

    Article  PubMed  CAS  Google Scholar 

  • Musch MW, Li YC and Chang EB. Angiotensin II directly regulates intestinal epithelial NHE3 in Caco2BBE cells. BMC Physiology 9:1–8, 2009.

    Article  Google Scholar 

  • Nagashio Y, Asaumi H, Watanabe S, Nomiyama Y, Taguchi M, Tashiro M, Sugaya T and Otsuki M. Angiotensin II type 1 receptor interaction is an important regulator for the development of pancreatic fibrosis in mice. Am J Physiol 287:G170–G177, 2004.

    CAS  Google Scholar 

  • Norris B, Gonzalez C, Concha J, Palacios S and Contreras G. Stimulatory effect of angiotensin II on electrolyte transport in canine tracheal epithelium. Gen Pharmacol 22:527–531, 1991.

    Article  PubMed  CAS  Google Scholar 

  • Omary MB, Lugea A, Lowe AW and Pandol SJ. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 117:50–59, 2007.

    Article  PubMed  CAS  Google Scholar 

  • Paul M, Poyan Mehr A and Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev 86:747–803, 2006.

    Article  PubMed  CAS  Google Scholar 

  • Pollare T, Lithell H and Berne C. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 321:868–873, 1989.

    Article  PubMed  CAS  Google Scholar 

  • Regoli M, Bendayan M, Fonzi L, Sernia C and Bertelli E. Angiotensinogen localization and secretion in the rat pancreas. J Endocrinol 179:81–89, 2003.

    Article  PubMed  CAS  Google Scholar 

  • Reinehr R, Zoller S, Klonowski-Stumpe H, Kordes C and Haussinger D. Effects of angiotensin II on rat pancreatic stellate cells. Pancreas 28:129–137, 2004.

    Article  PubMed  CAS  Google Scholar 

  • Schieffer B, Wirger A, Meybrunn M, Seitz S, Holtz J, Riede UN and Drexler H. Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. Circulation 89:2273–2282, 1994.

    Article  PubMed  CAS  Google Scholar 

  • Sealey JE, Catanzaro DF, Lavin TN, Gahnem F, Pitarresi T, Hu LF and Laragh JH. Specific prorenin/renin binding (ProBP). Identification and characterization of a novel membrane site. Am J Hypertens 9:491–502, 1996.

    Article  PubMed  CAS  Google Scholar 

  • Sernia C. Location and secretion of brain angiotensinogen. Regul Pept 57:1–18, 1995.

    Article  PubMed  CAS  Google Scholar 

  • Shimizu K. Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis. J Gastroenterol 43:823–832, 2008.

    Article  PubMed  CAS  Google Scholar 

  • Tahmasebi M, Puddefoot J, Inwang E and Vinson G. The tissue renin-angiotensin system in human pancreas. J Endocrinol 161:317–322, 1999.

    Article  PubMed  CAS  Google Scholar 

  • Tikellis C, Wookey P, Candido R, Andrikopoulos S, Thomas M and Cooper M. Improved islet morphology after blockade of the renin-angiotensin system in the ZDF rat. Diabetes 53:989–997, 2004.

    Article  PubMed  CAS  Google Scholar 

  • Tsang SW, Cheng HK, Leung PS. The role of the pancreatic renin-angiotensin system in acinar digestive enzyme secretion and in acute pancreatitis. Regul Pept 119:213–219, 2004.

    Article  PubMed  CAS  Google Scholar 

  • Wang R, Ramos C, Joshi I, Zagariya A, Pardo A, Selman M and Uhal BD. Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides. Am J Physiol 277:L1158–L1164, 1999.

    PubMed  CAS  Google Scholar 

  • Wong P, Lee S and Cheung W. Immunohistochemical colocalization of type II angiotensin receptors with somatostatin in rat pancreas. Regul Pept 117:195–205, 2004.

    Article  PubMed  CAS  Google Scholar 

  • Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210, 2008.

    Article  PubMed  CAS  Google Scholar 

  • Yamada T, Kuno A, Masuda K, Ogawa K, Sogawa M, Nakamura S, Ando T, Sano H, Nakazawa T, Ohara H, Nomura T, Joh T and Itoh M. Candesartan, an angiotensin II receptor antagonist, suppresses pancreatic inflammation and fibrosis in rats. J Pharmacol Exp Ther 307:17–23, 2003.

    Article  PubMed  CAS  Google Scholar 

  • Yin G, Yan C and Berk BC. Angiotensin II signaling pathways mediated by tyrosine kinases. Int J Biochem Cell Biol 35:780–783, 2003.

    Article  PubMed  CAS  Google Scholar 

  • Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H and Fukui H. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 34:745–750, 2001.

    Article  PubMed  CAS  Google Scholar 

  • Yoshikawa H, Kihara Y, Taguchi M, Yamaguchi T, Nakamura H and Otsuki M. Role of TGF-beta1 in the development of pancreatic fibrosis in Otsuka Long–Evans Tokushima Fatty rats. Am J Physiol Gastrointest Liver Physiol 282:G549–G558, 2002.

    PubMed  CAS  Google Scholar 

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  1. School of Biomedical Sciences Faculty of Medicine The Chinese University of Hong Kong, Shatin, Hong Kong, China

    Po Sing Leung PhD

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Leung, P.S. (2010). Pancreatic RAS. In: The Renin-Angiotensin System: Current Research Progress in The Pancreas. Advances in Experimental Medicine and Biology, vol 690. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9060-7_6

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