title: Regulator of G-protein signaling-5 is a marker of hepatic stellate cells and expression mediates response to liver injury.
abstract: 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.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Arya J
authors.initials: AJ
authors.lastname: Bahrami
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jagadambika J
authors.initials: JJ
authors.lastname: Gunaje
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hayes
authors.affiliation: Department of Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Riehle
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America; Department of Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Kenerson
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America; Department of Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Yeung
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America; Department of Cardiology, University of Washington, Seattle, Washington, United States of America; Center for Cardiovascular Biology and the Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: April S
authors.initials: AS
authors.lastname: Stempien-Otero
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America; Center for Cardiovascular Biology and the Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Mahoney
mesh_terms: D000818:Animals; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020710:RGS Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D019332:Endothelin-1; D020710:RGS Proteins; C491349:RGS5 protein, human; D034741:RNA, Small Interfering