Up-regulation of components of the renin-angiotensin system in the bile duct-ligated rat liver

Background & Aims: Angiotensin II (ANG II) has profibrotic actions in the heart and kidney, whereas blockade of the renin angiotensin system (RAS) attenuates injury. This study examines whether the RAS is present in the liver and examines its regulation in the bile duct-ligation model of hepatic fibrogenesis. Methods: Sham-operated and bile duct-ligated (BDL) Sprague-Dawley rats were studied. Gene and protein expression of hepatic renin, angiotensinogen, angiotensin-converting enzyme (ACE), and the angiotensin receptors AT(1) and AT(2) were assessed using real-time reverse-transcription polymerase chain reaction, in vitro autoradiography, and immunohistochemistry. Results: Angiotensinogen and renin messenger RNA were detected in sham liver but were not increased following BDL. Angiotensinogen protein was widely distributed in hepatocytes in both normal and injured livers, but in BDL livers, it was also expressed within areas of active fibrogenesis. Both ACE and AT(1). receptor genes were up-regulated following BDL. The low level of ACE activity in sham animals was significantly increased in areas of active fibrogenesis in BDL livers. The AT(1) receptor was present in both normal and diseased liver parenchyma, with increased AT(1) receptor binding seen in fibrotic areas in the diseased liver. The AT(2) receptor gene was not detected in normal or diseased liver. Conclusions: Key elements of the RAS are present in normal liver tissue, and there is major up-regulation of the system in the bile duct-ligated liver. These findings are in keeping with recent experimental studies that have demonstrated antifibrotic effects of RAS blockade, in the bile duct-ligated liver.