title: Activation of the renin-angiotensin system stimulates biliary hyperplasia during cholestasis induced by extrahepatic bile duct ligation.
abstract: Cholangiocyte proliferation is regulated in a coordinated fashion by many neuroendocrine factors through autocrine and paracrine mechanisms. The renin-angiotensin system (RAS) is known to play a role in the activation of hepatic stellate cells and blocking the RAS attenuates hepatic fibrosis. We investigated the role of the RAS during extrahepatic cholestasis induced by bile duct ligation (BDL). In this study, we used normal and BDL rats that were treated with control, angiotensin II (ANG II), or losartan for 2 wk. In vitro studies were performed in a primary rat cholangiocyte cell line (NRIC). The expression of renin, angiotensin-converting enzyme, angiotensinogen, and angiotensin receptor type 1 was evaluated by immunohistochemistry (IHC), real-time PCR, and FACs and found to be increased in BDL compared with normal rat. The levels of ANG II were evaluated by ELISA and found to be increased in serum and conditioned media of cholangiocytes from BDL compared with normal rats. Treatment with ANG II increased biliary mass and proliferation in both normal and BDL rats. Losartan attenuated BDL-induced biliary proliferation. In vitro, ANG II stimulated NRIC proliferation via increased intracellular cAMP levels and activation of the PKA/ERK/CREB intracellular signaling pathway. ANG II stimulated a significant increase in Sirius red staining and IHC for fibronectin that was blocked by angiotensin receptor blockade. In vitro, ANG II stimulated the gene expression of collagen 1A1, fibronectin 1, and IL-6. These results indicate that cholangiocytes express a local RAS and that ANG II plays an important role in regulating biliary proliferation and fibrosis during extraheptic cholestasis.
authors: Scott & White Digestive Disease Research Center, Temple, Texas; and.
authors: Syeda H
authors: SH
authors: Afroze
authors: Scott & White Digestive Disease Research Center, Temple, Texas; and.
authors: Md Kamruzzaman
authors: MK
authors: Munshi
authors: Department of Internal Medicine, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas.
authors: Allyson K
authors: AK
authors: Martínez
authors: Department of Internal Medicine, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas.
authors: Mohammad
authors: M
authors: Uddin
authors: Department of Internal Medicine, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas.
authors: Maté
authors: M
authors: Gergely
authors: Department of Internal Medicine, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas.
authors: Claudia
authors: C
authors: Szynkarski
authors: Department of Internal Medicine, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas.
authors: Micheleine
authors: M
authors: Guerrier
authors: Department of Internal Medicine, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas.
authors: Damir
authors: D
authors: Nizamutdinov
authors: Department of Internal Medicine, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas.
authors: David
authors: D
authors: Dostal
authors: Central Texas Veterans Health Care System, Temple, Texas; Scott & White Digestive Disease Research Center, Temple, Texas; and Department of Internal Medicine, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas sglaser@tamu.edu.
authors: Shannon
authors: S
authors: Glaser
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D017734:Bile Ducts, Extrahepatic / Q000187:drug effects* / Q000473:pathology / Q000601:surgery*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D001651:Cholestasis, Extrahepatic / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D006965:Hyperplasia; D008026:Ligation; D019808:Losartan / Q000494:pharmacology; D008297:Male; D011916:Rats, Inbred F344; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000804:Angiotensin II; D019808:Losartan
keywords: angiotensin; bile duct ligation; cholangiocyte; renin-angiotensin system