Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

The FASEB JournalVolume 29, Issue 3 p. 1029-1042 Research CommunicationFree to Read Selective delivery of IFN-γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis Fariba Poosti, Corresponding Author Fariba Poosti f.poosti@umcg.nl Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, Groningen, The NetherlandsCorrespondence: Department of Pathology and Medical Biology-Pathology (HPC: EA10), University Medical Center Groningen, University of Groningen, Groningen, P.O. Box 30001, 9700 RB, Groningen, The Netherlands. E-mail: f.poosti@umcg.nl (F.P.); j.l.hillebrands@umcg.nl (J.-L.H.)Search for more papers by this authorRuchi Bansal, Ruchi Bansal MIRA Institute, University of Twente, Enschede, The NetherlandsSearch for more papers by this authorSaleh Yazdani, Saleh Yazdani MIRA Institute, University of Twente, Enschede, The NetherlandsSearch for more papers by this authorJai Prakash, Jai Prakash MIRA Institute, University of Twente, Enschede, The NetherlandsSearch for more papers by this authorEduard Post, Eduard Post Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorPieter Klok, Pieter Klok Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorJacob van den Born, Jacob van den Born Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorMartin H. de Borst, Martin H. de Borst Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorHarry van Goor, Harry van Goor Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorKlaas Poelstra, Klaas Poelstra Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorJan-Luuk Hillebrands, Jan-Luuk Hillebrands Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, Groningen, The NetherlandsSearch for more papers by this author Fariba Poosti, Corresponding Author Fariba Poosti f.poosti@umcg.nl Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, Groningen, The NetherlandsCorrespondence: Department of Pathology and Medical Biology-Pathology (HPC: EA10), University Medical Center Groningen, University of Groningen, Groningen, P.O. Box 30001, 9700 RB, Groningen, The Netherlands. E-mail: f.poosti@umcg.nl (F.P.); j.l.hillebrands@umcg.nl (J.-L.H.)Search for more papers by this authorRuchi Bansal, Ruchi Bansal MIRA Institute, University of Twente, Enschede, The NetherlandsSearch for more papers by this authorSaleh Yazdani, Saleh Yazdani MIRA Institute, University of Twente, Enschede, The NetherlandsSearch for more papers by this authorJai Prakash, Jai Prakash MIRA Institute, University of Twente, Enschede, The NetherlandsSearch for more papers by this authorEduard Post, Eduard Post Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorPieter Klok, Pieter Klok Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorJacob van den Born, Jacob van den Born Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorMartin H. de Borst, Martin H. de Borst Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorHarry van Goor, Harry van Goor Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorKlaas Poelstra, Klaas Poelstra Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorJan-Luuk Hillebrands, Jan-Luuk Hillebrands Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, Groningen, The NetherlandsSearch for more papers by this author First published: 02 December 2014 https://doi.org/10.1096/fj.14-258459Citations: 4 This article includes supplemental data. Please visit http://www.fasebj.org to obtain this information. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat 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-PEGIFN-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.—Poosti, F., Bansal, R., Yazdani, S., Prakash, J., Post, E., Klok, P., vanden Born J. deBorst M.H. vanGoor H. Poelstra K. Hillebrands, J.-L. Selective delivery of IFN-γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis. FASEB J. 29, 1029–1042 (2015). www.fasebj.org Citing Literature Supporting Information Filename Description fsb2029003028-sup-0001.epsapplication/eps, 834.9 KB Supplementary material fsb2029003028-sup-0002.docxapplication/docx, 12.9 KB Supplementary material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume29, Issue3March 2015Pages 1029-1042 RelatedInformation