title: Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor.
abstract: The expansion of the fibroblast pool is a critical step in organ fibrosis, but the mechanisms driving expansion remain to be fully clarified. We previously showed that lysophosphatidic acid (LPA) signaling through its receptor LPA1expressed on fibroblasts directly induces the recruitment of these cells. Here we tested whether LPA-LPA1signaling drives fibroblast proliferation and activation during the development of renal fibrosis. LPA1-deficient (LPA1-/-) or -sufficient (LPA1+/+) mice were crossed to mice with green fluorescent protein expression (GFP) driven by the type I procollagen promoter (Col-GFP) to identify fibroblasts. Unilateral ureteral obstruction-induced increases in renal collagen were significantly, though not completely, attenuated in LPA1-/-Col-GFP mice, as were the accumulations of both fibroblasts and myofibroblasts. Connective tissue growth factor was detected mainly in tubular epithelial cells, and its levels were suppressed in LPA1-/-Col-GFP mice. LPA-LPA1signaling directly induced connective tissue growth factor expression in primary proximal tubular epithelial cells, through a myocardin-related transcription factor-serum response factor pathway. Proximal tubular epithelial cell-derived connective tissue growth factor mediated renal fibroblast proliferation and myofibroblast differentiation. Administration of an inhibitor of myocardin-related transcription factor/serum response factor suppressed obstruction-induced renal fibrosis. Thus, targeting LPA-LPA1signaling and/or myocardin-related transcription factor/serum response factor-induced transcription could be promising therapeutic strategies for renal fibrosis.
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan; Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan. Electronic address: norin0826@yahoo.co.jp.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Sakai
authors.affiliation: Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: Division of Nephrology, Department of Medicine, Center for Lung Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA; Biogen, Cambridge, Massachusetts, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lagares
authors.affiliation: Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan; Department of Laboratory Medicine and Nephrology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Fibrosis Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: amtager@mgh.harvard.edu.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008246:Lysophospholipids / Q000494:pharmacology*; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C526318:CCN2 protein, mouse; D024042:Collagen Type I; D008246:Lysophospholipids; C511173:Mrtfa protein, mouse; D049368:Receptors, Lysophosphatidic Acid; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; C503315:myocardin-related transcription factor B, mouse; D055513:Connective Tissue Growth Factor; D049452:Green Fluorescent Proteins; C032881:lysophosphatidic acid
keywords: CTGF; LPA(1); fibroblast; fibrosis