title: Selective delivery of IFN-γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis.
abstract: Renal fibrosis leads to end-stage renal disease demanding renal replacement therapy because no adequate treatment exists. IFN-γ is an antifibrotic cytokine that may attenuate renal fibrosis. Systemically administered IFN-γ causes side effects that may be prevented by specific drug targeting. Interstitial myofibroblasts are the effector cells in renal fibrogenesis. Here, we tested the hypothesis that cell-specific delivery of IFN-γ to platelet-derived growth factor receptor β (PDGFRβ)-expressing myofibroblasts attenuates fibrosis in an obstructive nephropathy [unilateral ureteral obstruction (UUO)] mouse model. PEGylated IFN-γ conjugated to PDGFRβ-recognizing peptide [(PPB)-polyethylene glycol (PEG)-IFN-γ] was tested in vitro and in vivo for antifibrotic properties and compared with free IFN-γ. PDGFRβ expression was >3-fold increased (P < 0.05) in mouse fibrotic UUO kidneys and colocalized with α-smooth muscle actin-positive (SMA(+)) myofibroblasts. In vitro, PPB-PEG-IFN-γ significantly inhibited col1a1, col1a2, and α-SMA mRNA expression in TGF-β-activated NIH3T3 fibroblasts (P < 0.05). In vivo, PPB-PEG-IFN-γ specifically accumulated in PDGFRβ-positive myofibroblasts. PPB-PEG-IFN-γ treatment significantly reduced renal collagen I, fibronectin, and α-SMA mRNA and protein expression. Compared with vehicle treatment, PPB-PEG-IFN-γ preserved tubular morphology, reduced interstitial T-cell infiltration, and attenuated lymphangiogenesis (all P < 0.05) without affecting peritubular capillary density. PPB-PEG-IFN-γ reduced IFN-γ-related side effects as manifested by reduced major histocompatibility complex class II expression in brain tissue (P < 0.05 vs. free IFN-γ). Our findings demonstrate that specific targeting of IFN-γ to PDGFRβ-expressing myofibroblasts attenuates renal fibrosis and reduces systemic adverse effects.
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands f.poosti@umcg.nl j.l.hillebrands@umcg.nl.
authors.forename: Fariba
authors.initials: F
authors.lastname: Poosti
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Bansal
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands.
authors.forename: Saleh
authors.initials: S
authors.lastname: Yazdani
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands.
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands.
authors.forename: Eduard
authors.initials: E
authors.lastname: Post
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Klok
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands.
authors.forename: Jacob
authors.initials: J
authors.lastname: van den Born
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands.
authors.forename: Martin H
authors.initials: MH
authors.lastname: de Borst
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands.
authors.forename: Klaas
authors.initials: K
authors.lastname: Poelstra
authors.affiliation: *Department of Pathology and Medical Biology, Division of Pathology, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, and Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands; and MIRA Institute, University of Twente, Enschede, The Netherlands f.poosti@umcg.nl j.l.hillebrands@umcg.nl.
authors.forename: Jan-Luuk
authors.initials: JL
authors.lastname: Hillebrands
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D005355:Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D016898:Interferon-alpha / Q000494:pharmacology*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D041681:NIH 3T3 Cells; D011092:Polyethylene Glycols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D020797:Receptor, Platelet-Derived Growth Factor beta; C100416:peginterferon alfa-2a
keywords: PDGFRβ; drug targeting; kidney; unilateral ureteral obstruction