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.

Local Renin-Angiotensin System at Liver and Crosstalk with Hepatic Diseases

“…One of the recent data shows that local RAS components were found at cholangiocytes [2]. Hepatic Kupffer cells [3] and nuclear region of hepatocytes [4] also locally produce angiotensin-II (Ang-II) [9].…”

“…It is surprising that renin expression in the female is higher than male in liver tissue of both mice and rats [7]. Furthermore, its expression was found at liver cells such as cholangiocytes, hepatocytes, and hepatic stellate cells (HSC) [9]. Renin receptor was reported to have low-level expression mRNA at liver and kidney, but the high level of the heart, brain, and placenta.…”

“…So, there is reported to have some prophylactic effects against to liver failure [7]. One of the previous studies noticed that active RAS blocking by either angiotensin-converting enzyme (ACE) or AT1 inhibition led to attenuate liver fibrosis by suppressing HCS and hepatic TGF-β1 in chronic liver injury [9]. The component of local RAS was found in the liver of obese and type-2 diabetes patients.…”

“…Additionally, MAPK, Ang-II can activate nuclear factor-κB (NF-κB) [20]. Ang-II gives rise to trigger proliferation by stimulation of the cAMP signal pathway [9] as well. It is noticed that human fibrotic liver samples were found less AT1 expressing at hepatocytes, but high expressing in hepatic stellate cells (HSCs), vascular endothelium, and bile duct epithelium.…”

“…It is noticed that human fibrotic liver samples were found less AT1 expressing at hepatocytes, but high expressing in hepatic stellate cells (HSCs), vascular endothelium, and bile duct epithelium. The local RAS-induced HSC via AT1 and activation of NADPH oxidase results in fibrotic liver, and cholangiocyte proliferation by AT1 triggering a cAMP, PKA, ERK1/2, and pCREB-dependent signaling pathway [9]. Hepatic stellate cell (HSC) is the most effective cell type of liver to the deposit of connective tissue at respond of liver injury.…”