Regulator of G-protein signaling-5 is a marker of hepatic stellate cells and expression mediates response to liver injury

• Published in: PloS one 2014-10, Vol.9 (10), p.e108505
• Main Authors: Bahrami, Arya J, Gunaje, Jagadambika J, Hayes, Brian J, Riehle, Kimberly J, Kenerson, Heidi L, Yeung, Raymond S, Stempien-Otero, April S, Campbell, Jean S, Mahoney, Jr, William M
• Format: Article
• Language: English
• Subjects: Activation; Angiotensin; Angiotensin II; Animals; Biology and life sciences; Blood pressure; Carbon tetrachloride; Cell Line; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - pathology; Collagen; Contraction; Cytokines; Disease Models, Animal; Endothelin; Endothelin 1; Endothelin-1 - metabolism; Extracellular matrix; Fatty acids; Fibrosis; G protein-coupled receptors; Gene Expression; Gene Expression Regulation; Growth factors; Hematopoietic Stem Cells - metabolism; Hepatic Stellate Cells - metabolism; Homeostasis; Hypertension; Hypertrophy; Injuries; Kinases; Laboratory animals; Liver; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Liver diseases; Liver Diseases - genetics; Liver Diseases - metabolism; Liver Diseases - pathology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Medicine and Health Sciences; Mice; Mice, Knockout; Mice, Transgenic; Muscle contraction; Muscles; Pathology; Pericytes; Proteins; RGS Proteins - genetics; RNA, Small Interfering - genetics; Rodents; Signal Transduction; Signaling; Smooth muscle; Stellate cells; Stem cells; Surgery; Tumor necrosis factor-TNF; Vasoactive agents
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0108505

Liver fibrosis is mediated by hepatic stellate cells (HSCs), which respond to a variety of cytokine and growth factors to moderate the response to injury and create extracellular matrix at the site of injury. G-protein coupled receptor (GPCR)-mediated signaling, via endothelin-1 (ET-1) and angiotensin II (AngII), increases HSC contraction, migration and fibrogenesis. Regulator of G-protein signaling-5 (RGS5), an inhibitor of vasoactive GPCR agonists, functions to control GPCR-mediated contraction and hypertrophy in pericytes and smooth muscle cells (SMCs). Therefore we hypothesized that RGS5 controls GPCR signaling in activated HSCs in the context of liver injury. In this study, we localize RGS5 to the HSCs and demonstrate that Rgs5 expression is regulated during carbon tetrachloride (CCl4)-induced acute and chronic liver injury in Rgs5LacZ/LacZ reporter mice. Furthermore, CCl4 treated RGS5-null mice develop increased hepatocyte damage and fibrosis in response to CCl4 and have increased expression of markers of HSC activation. Knockdown of Rgs5 enhances ET-1-mediated signaling in HSCs in vitro. Taken together, we demonstrate that RGS5 is a critical regulator of GPCR signaling in HSCs and regulates HSC activation and fibrogenesis in liver injury.