Candesartan, an angiotensin II receptor antagonist, suppresses pancreatic inflammation and fibrosis in rats.
Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate fibrosis in the kidney, heart, and liver by suppressing transforming growth factor-beta1 mRNA and decreasing production of extracellular matrix proteins. We recently demonstrated that lisinopril, an angiotensin-converting enzyme inhibitor, alleviates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats. The involvement of angiotensin II receptor and its receptor interaction in the pathogenesis of spontaneous chronic pancreatitis was assessed in this model. Candesartan, an angiotensin II receptor antagonist, was administered in drinking water (10.5, 42, or 125 mg/l) to 10-week-old male WBN/Kob rats for 10 weeks and inflammatory parameters, fibrosis, and gene expression of renin-angiotensin system components and transforming growth factor-beta1 were assessed in the pancreas. Immunostaining for alpha-smooth muscle actin was also performed. Candesartan significantly suppressed decrease in pancreatic weight and increases in pancreatic myeloperoxidase activity, hydroxyproline content, ratio of fibrous tissue, histologic scores, and ratio of alpha-smooth muscle actin-positive cells (activated pancreatic stellate cells) at 20 weeks. The high dose enhanced the expression of angiotensinogen and angiotensin II receptor type 2 mRNA and suppressed the overexpression of transforming growth factor-beta1 mRNA. The conclusion is that candesartan alleviates chronic pancreatitis and fibrosis by suppressing the overexpression of transforming growth factor-beta1, resulting in prevention of activation of pancreatic stellate cells in male WBN/Kob rats. We propose that angiotensin II receptor type 1 antagonists may be useful for the treatment of chronic pancreatitis involving angiotensin II interaction with its receptor.
Yamada
Tamaki
T
Department of Comprehensive Medicine, Internal Medicine, and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan. yamtmaki@med.nagoya-cu.ac.jp
Kuno
Atsushi
A
Masuda
Kazuhiko
K
Ogawa
Kumiko
K
Sogawa
Mitsue
M
Nakamura
Soichi
S
Ando
Tomoaki
T
Sano
Hitoshi
H
Nakazawa
Takahiro
T
Ohara
Hirotaka
H
Nomura
Tomoyuki
T
Joh
Takashi
T
Itoh
Makoto
M
D000199:Actins / Q000032:analysis; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000627:therapeutic use; D001562:Benzimidazoles / Q000097:blood / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001835:Body Weight / Q000187:drug effects; D005355:Fibrosis / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010195:Pancreatitis / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000096:biosynthesis / Q000235:genetics; D013777:Tetrazoles / Q000097:blood / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics
D000199:Actins; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D009195:Peroxidase; D006909:Hydroxyproline; C081643:candesartan