Angiotensin II mediates acinar cell apoptosis during the development of rat pancreatic fibrosis by AT1R.
OBJECTIVE
The mechanisms of pancreatic fibrosis were not fully elucidated. Apoptosis has been suggested to be involved in the progression of pancreatic fibrosis. It has been reported that the renin-angiotensin system (RAS) plays a crucial role in the formation of fibrosis, including in the kidney, heart, and liver. We recently reported that the angiotensin II type I receptor (AT1R) antagonist losartan has been able to alleviate the pancreatic fibrosis in the rat model, indicating angiotensin II participated in the progression of pancreatic fibrosis. In present study, the possible effects of angiotensin II-mediated apoptosis of pancreatic acinar cells were investigated in rat pancreatic fibrosis induced by trinitrobenzene sulfonic acid (TNBS) by AT1R, with special reference to the losartan administration.


METHODS
Male Sprague-Dawley rats (200-300 g) were randomly divided into a normal group, a control group, and a losartan-treatment group. Pancreatic fibrosis was induced by infusion of 2% TNBS into the pancreatic duct. Rats were treated with losartan (10 mg/kg) by gavage daily in the losartan-treatment group and the same volume of sterile distilled water was administered to the control group. All treatments started on the first day and ended 8 weeks after the operation. On day 3 and at weeks 1, 2, 3, 4, and 8, the histologic changes of the pancreas were examined by hematoxylin and eosin staining, and pancreatic acinar cell apoptosis was investigated by using electron microscopy and terminal deoxynucleotidyl transferase UTP nick end labeling (TUNEL), indicated by the apoptotic index (AI). Expressions of Bax, Bak, and Bcl-2 mRNA in the pancreas were detected by reverse transcriptase polymerase chain reaction (RT-PCR) on day 3 and at weeks 1, 2, 3, and 4.


RESULTS
Compared with the control group, losartan treatment significantly alleviated the histologic abnormalities, including infiltration of inflammatory cells and acinar cells atrophy. In the control group, a typical morphologic presentation of acinar cell apoptosis was seen either with electron microscopy or TUNEL staining. The AI was increased in pancreatic tissue. Meanwhile, Bax and Bak mRNA expression was increased, but Bcl-2 mRNA expression was decreased, as compared with the normal group. The administration of losartan resulted in inhibition of acinar cell apoptosis and down-regulation of Bax, Bak, and Bcl-2 mRNA expression. The Bax/Bcl-2 ratio was lower in losartan-treated rats than in control rats.


CONCLUSIONS
Losartan prevents apoptosis of pancreatic acinar cell by blocking AT1R during the development of pancreatic fibrosis. This action may be associated with its regulation of apoptosis-associated genes, such as Bax, Bak, and Bcl-2 mRNA. The results of present study suggest that angiotensin II probably mediates pancreatic acinar cell apoptosis during the course of pancreatic fibrosis.
Wang
Xing-Peng
XP
Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China. xpwcn@public7.sta.net.cn
Zhang
Ruling
R
Wu
Kai
K
Wu
Liying
L
Dong
Yuwei
Y
D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics; D020287:In Situ Nick-End Labeling / Q000379:methods; D019808:Losartan / Q000494:pharmacology; D008297:Male; D010179:Pancreas / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D010183:Pancreatic Ducts / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014302:Trinitrobenzenesulfonic Acid / Q000009:adverse effects
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D014302:Trinitrobenzenesulfonic Acid; D019808:Losartan