title: Interferon gamma peptidomimetic targeted to interstitial myofibroblasts attenuates renal fibrosis after unilateral ureteral obstruction in mice.
abstract: Renal fibrosis cannot be adequately treated since anti-fibrotic treatment is lacking. Interferon-γ is a pro-inflammatory cytokine with anti-fibrotic properties. Clinical use of interferon-γ is hampered due to inflammation-mediated systemic side effects. We used an interferon-γ peptidomimetic (mimγ) lacking the extracellular IFNγReceptor recognition domain, and coupled it to the PDGFβR-recognizing peptide BiPPB. Here we tested the efficacy of mimγ-BiPPB (referred to as "Fibroferon") targeted to PDGFβR-overexpressing interstitial myofibroblasts to attenuate renal fibrosis without inducing inflammation-mediated side effects in the mouse unilateral ureter obstruction model.Unilateral ureter obstruction induced renal fibrosis characterized by significantly increased α-SMA, TGFβ1, fibronectin, and collagens I and III protein and/or mRNA expression. Fibroferon treatment significantly reduced expression of these fibrotic markers. Compared to full-length IFNγ, anti-fibrotic effects of Fibroferon were more pronounced. Unilateral ureter obstruction-induced lymphangiogenesis was significantly reduced by Fibroferon but not full-length IFNγ. In contrast to full-length IFNγ, Fibroferon did not induce IFNγ-related side-effects as evidenced by preserved low-level brain MHC II expression (similar to vehicle), lowered plasma triglyceride levels, and improved weight gain after unilateral ureter obstruction.In conclusion, compared to full-length IFNγ, the IFNγ-peptidomimetic Fibroferon targeted to PDGFβR-overexpressing myofibroblasts attenuates renal fibrosis in the absence of IFNγ-mediated adverse effects.
authors: Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Microbiology and Immunology, Laboratory of Molecular Immunology, Rega Institute, KU Leuven, Belgium.
authors: Fariba
authors: F
authors: Poosti
authors: Department of Biomaterials Science and Technology, Division of Targeted Therapeutics, MIRA Institute, University of Twente, Enschede, The Netherlands.
authors: Ruchi
authors: R
authors: Bansal
authors: Department of Biomaterials Science and Technology, Division of Targeted Therapeutics, MIRA Institute, University of Twente, Enschede, The Netherlands.
authors: Saleh
authors: S
authors: Yazdani
authors: Department of Biomaterials Science and Technology, Division of Targeted Therapeutics, MIRA Institute, University of Twente, Enschede, The Netherlands.
authors: Jai
authors: J
authors: Prakash
authors: Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands.
authors: Leonie
authors: L
authors: Beljaars
authors: Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Jacob
authors: J
authors: van den Born
authors: Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Martin H
authors: MH
authors: de Borst
authors: Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Harry
authors: H
authors: van Goor
authors: Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Jan-Luuk
authors: JL
authors: Hillebrands
authors: Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands.
authors: Klaas
authors: K
authors: Poelstra
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D007371:Interferon-gamma / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology*; D042583:Lymphangiogenesis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000378:metabolism*; D057786:Peptidomimetics / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000188:drug therapy*
chemical_list: D057786:Peptidomimetics; D007371:Interferon-gamma; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: Pathology Section; drug targeting; fibrosis; interferon gamma; kidney; myofibroblast