Pancreatic Renin-Angiotensin System

Po Sing Leung
Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong. Shatin,
Hong Kong
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 round-
table 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

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JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 4, No. 2 – March 2003
90
the administration of RAS inhibitors, such as
antagonist for Ang II receptors in cerulein-
induced 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 insulin-
secreting beta cells. In addition, ATreceptor
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 ATreceptor is the
enzyme insulin-regulated aminopeptidase,
suggesting its potential role in glucose uptake
[15]. Whether or not the ATreceptor 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.
Key words Cystic Fibrosis; Diabetes
Mellitus;
Islets
of
Langerhans
Transplantation; Pancreas; Pancreatitis;
Renin-Angiotensin System
Abbreviations ACE: angiotensin converting-
enzyme; Ang: angiotensin; AT: angiotensin
receptor type; PET: pancreatic endocrine
tumor; RAS: renin-angiotensin system
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)
Correspondence
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 address: psleung@cuhk.edu.hk

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JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 4, No. 2 – March 2003
91
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