title: Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis.
abstract: Fibrinogen (Fg) has been implicated in the pathogenesis of several fibrotic disorders by acting as a profibrotic ligand for a variety of cellular surface receptors and by modulating the provisional fibrin matrix formed after injury. We demonstrated increased renal Fg expression after unilateral ureteral obstruction and folic acid (FA) nephropathy in mice, respectively. Urinary Fg excretion was also increased in FA nephropathy. Using in vitro and in vivo approaches, our results suggested that IL-6 mediates STAT3 activation in kidney fibrosis and that phosphorylated (p)STAT3 binds to Fgα, Fgβ, and Fgγ promoters in the kidney to regulate their transcription. Genetically modified Fg heterozygous mice (∼75% of normal plasma Fg levels) exhibited only 3% kidney interstitial fibrosis and tubular atrophy after FA nephropathy compared with 24% for wild-type mice. Fibrinogenolysis through Ancrod administration after FA reduced interstitial fibrosis more than threefold compared with vehicle-treated control mice. Mechanistically, we show that Fg acts synergistically with transforming growth factor (TGF)-β1 to induce fibroblast proliferation and activates TGF-β1/pSMAD2 signaling. This study offers increased understanding of Fg expression and molecular interactions with TGF-β1 in the progression to kidney fibrosis and, importantly, indicates that fibrinogenolytics like Ancrod present a treatment opportunity for a yet intractable disease.
authors.affiliation: Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Florin L
authors.initials: FL
authors.lastname: Craciun
authors.affiliation: Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Amrendra K
authors.initials: AK
authors.lastname: Ajay
authors.affiliation: Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Dana
authors.initials: D
authors.lastname: Hoffmann
authors.affiliation: Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Janani
authors.initials: J
authors.lastname: Saikumar
authors.affiliation: Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Steven L
authors.initials: SL
authors.lastname: Fabian
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Vanesa
authors.initials: V
authors.lastname: Bijol
authors.affiliation: Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Humphreys
authors.affiliation: Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts; Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts; and Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, Massachusetts vvaidya@partners.org.
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Vaidya
mesh_terms: D000721:Ancrod / Q000627:therapeutic use; D000818:Animals; D018450:Disease Progression; D005340:Fibrinogen / Q000378:metabolism* / Q000652:urine; D005355:Fibrosis; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000473:pathology
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C494087:Stat3 protein, mouse; D053773:Transforming Growth Factor beta1; D005340:Fibrinogen; D000721:Ancrod
keywords: Ancrod; chronic kidney disease; fibrinogen; kidney fibrosis; transforming growth factor-β1