The role of the pancreatic renin–angiotensin system in acinar digestive enzyme secretion and in acute pancreatitis
Introduction
Among the neurohormonal regulators, cholecystokinin (CCK) and acetylcholine are two well-known gastrointestinal hormone and neural agonist, respectively, for inducing the release of pancreatic digestive enzymes [1], [2], [3]. Other peptide hormones such as somatostatin, pancreatic polypeptide and peptide YY are known to inhibit the exocrine pancreatic secretion [4], [5], [6]. Interestingly, the peptide hormone angiotensin II (Ang II) may be a key mediator for exocrine pancreatic secretion in response to food components [7]. The notion for an existence of a local renin–angiotensin system (RAS) in the pancreas was previously proposed in the dog [8], [9], rodents [10], [11] and human [12]. The expression and regulation of a local pancreatic RAS and its potential roles in exocrine and endocrine secretions have been recently reviewed [13], [14]. In the exocrine pancreas, Ang II receptors (AT1 and AT2) are predominantly localized in the pancreatic ducts, blood vessels and acinar cells [15]. In this regard, our recent studies have showed that experimental pancreatitis upregulates the RAS components in the pancreas [16], [17]. Prophylactic administration of saralasin, a nonspecific AT1/AT2 antagonist, was protective against acute pancreatitis [18]. Activation of the pancreatic RAS could be linked to an enhanced oxidative stress thus leading to pancreatic injury [19]. In addition, RAS inhibition by an angiotensin converting enzyme (ACE) blocker attenuates pancreatic inflammation, further indicating a role of pancreatic RAS blockade in pancreatitis [20]. Nevertheless, the role of the pancreatic RAS in acinar digestion secretion and in acute pancreatitis remains unknown. The present study is therefore designed to demonstrate, with an in-vitro system, the presence of RAS components in acinar cells and to elucidate its potential role in digestive enzyme secretion as well as in acute pancreatitis.
Section snippets
Animal models
Sprague–Dawley rats (90–100 g) aged 28 days were employed and starved overnight in the Laboratory Animal Services Centre of the Chinese University of Hong Kong. Ethical approval for the experimental procedures was obtained from the Animal Experimentation Ethics Committee of the Chinese University of Hong Kong. Induction of experimental pancreatitis has been described previously [16], [17], [18], [19]. Briefly, rats were randomly assigned into five experimental groups (control, inhibitor
Ang II-stimulated release of α-amylase and lipase from pancreatic acini
The isolated pancreatic acini were confirmed to be functional as the CCK-octapeptide could induce a concentration-dependent release of α-amylase (Fig. 1A) and lipase (Fig. 1B) at doses ranging from 0.1 to 100 nM after 30-min incubation. Besides the CCK-octapeptide, Ang II was also demonstrated to stimulate a dose-dependent release of acinar secretion of amylase (Fig. 2A) and lipase (Fig. 2B). However, the potency of Ang II was not as high as the CCK-octapeptide.
Effects of Ang II receptor inhibitors on pancreatic digestive enzyme secretion
Pre-incubation with the selective
Discussion
Pancreatic acini are responsible for the exocrine secretion of digestive enzymes, which are subject to the regulation of gastrointestinal peptides such as CCK and secretin, and neurotransmitters such as acetylcholine as well as a number of other factors [23]. In this study, the potential role of the peptide Ang II in regulating digestive enzyme secretion from the exocrine pancreas was explored in isolated pancreatic acini. Dispersed pancreatic acinar cells were responsive to the CCK-octapeptide
Acknowledgments
We would like to gratefully acknowledge the financial support by the Competitive Earmarked Research Grant from the Research Grants Council of Hong Kong (Project #CUHK 4075/00M and 4116/01M). Losartan was kindly provided by Merck, New Jersey, USA.
References (32)
- et al.
Neural hormonal regulation of exocrine pancreatic secretion
Pancreatology
(2001) Integrated actions of cholecystokinin on the gastrointestinal tract: use of the cholecystokinin bioassay
Gastroenterol. Clin. North Am.
(1989)- et al.
Effects of an antral mucosectomy, L-364,718 and atropine on cephalic phase of gastric and pancreatic secretion in dogs
Gastroenterology
(1990) - et al.
Feedback regulation of pancreatic secretion of peptide YY
Peptides
(2002) - et al.
Characterization of angiotensin II receptor subtypes in pancreatic acinar AR42J cells
Peptides
(1995) - et al.
A local pancreatic renin–angiotensin system: endocrine and exocrine roles
Int. J. Biochem. Cell Biol.
(2003) - et al.
Regulated expression of pancreatic renin–angiotensin system in experimental pancreatitis
Mol. Cell. Endocrinol.
(2000) - et al.
Changes of angiotensin-converting enzyme activity in the pancreas of chronic hypoxia and acute pancreatitis
Int. J. Biochem. Cell Biol.
(2003) - et al.
Differential effects of saralasin and ramiprilat, the inhibitors of renin–angiotensin system, on cerulein-induced acute pancreatitis
Regul. Pept.
(2003) - et al.
Angiotensin-converting enzyme inhihitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats
Gastroenterology
(2003)
Characterization of a functional AT1A angiotensin receptor in pancreatoma AR4-2J cells
Peptides
Prophylactic and therapeutic treatments with AT1 and AT2 receptor antagonists and their effects on changes in the severity of pancreatitis
Int. J. Biochem. Cell Biol.
Renal expression of angiotensin type 2 (AT2) receptors during kidney damage
Kidney Int. Suppl.
Angiotensin II activates nuclear transcription factor-kappa B through AT1 and AT2 receptors
Kidney Int.
Pathophysiological role of cholecystokinin in humans
J. Gastroenterol. Hepatol.
Intestinal somatostatin function
Adv. Exp. Med. Biol.
Cited by (61)
Alteration of the renin-angiotensin system in caerulein induced acute pancreatitis in the mouse
2015, PancreatologyCitation Excerpt :Moreover, experimental results indicate that unbalanced Ang II/Ang-(1–7) is associated with inflammation, and a change in Ang II/Ang-(1–7) level is closely related to the ratio of ACE2/ACE enzyme levels. In the pancreas, RAS is known to regulate digestive enzyme secretion [19,20] and several studies have shown the involvement of RAS in acute pancreatitis [19–26]. However, as previously described, these studies also describe contradicting roles for the various RAS components with regards to pancreatitis and the ensuing inflammatory response.
Valsartan, a specific angiotensin II receptor blocker, inhibits pancreatic fluid secretion via vagal afferent pathway in conscious rats
2012, Regulatory PeptidesCitation Excerpt :For example, AT1 receptor activation is involved in bicarbonate secretion in isolated dog pancreatic epithelial cells and cystic fibrosis pancreatic cell cultures [7]. Moreover, exogenous addition of angiotensin II stimulates a release of amylase and lipase from isolated pancreatic acini [8]. However, effects of RAS on regulating pancreatic exocrine secretion under physiological conditions are poorly defined, and these observations in vivo are controversial [11,12].
Severe acute pancreatitis is associated with upregulation of the ACE2-angiotensin-(1-7)-Mas axis and promotes increased circulating angiotensin-(1-7)
2012, PancreatologyCitation Excerpt :Studies have confirmed that local pancreatic RAS is closely related to acute pancreatitis. In the pancreatic exocrine gland AT1 and AT2 are expressed in the pancreatic duct, blood vessels, acinar cells and in isolated rat pancreatic acini, and their expression was increased during pancreatitis [12]. The addition of exogenous Ang-II can lead to a dose-dependent release of digestive enzymes in acinar cells, whereas treatment with the selective AT1 receptor antagonist losartan can significantly inhibit the secretion of digestive enzymes of acinar cells in the normal or pancreatitis model.
Can we expect progress in the treatment of fibrosis in the course of chronic pancreatitis?
2011, Advances in Medical SciencesThe Angiotensin AT<inf>2</inf> Receptor: Froma Binding Site to a Novel Therapeutic Target
2022, Pharmacological Reviews