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

Fariba Poosti*, Ruchi Bansal, Saleh Yazdani, Jai Prakash, Eduard Post, Pieter Klok, Jacob van den Born, Martin H. de Borst, Harry van Goor, Klaas Poelstra, Jan-Luuk Hillebrands

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

43 Citations (Scopus)

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.-Poosti, F., Bansal, R., Yazdani, S., Prakash, J., Post, E., Klok, P., van den Born, J., de Borst, M. H., van Goor, H., Poelstra, K., and Hillebrands, J.-L. Selective delivery of IFN-γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis.

Original languageEnglish
Pages (from-to)1029-1042
Number of pages14
JournalThe FASEB Journal
Volume29
Issue number3
DOIs
Publication statusPublished - Mar-2015

Keywords

  • drug targeting
  • PDGFR beta
  • kidney
  • unilateral ureteral obstruction
  • UNILATERAL URETERAL OBSTRUCTION
  • CHRONIC KIDNEY-DISEASE
  • NUCLEAR-LOCALIZATION SEQUENCE
  • TO-MESENCHYMAL TRANSITION
  • INTERFERON-GAMMA
  • GROWTH-FACTOR
  • THERAPEUTIC TARGETS
  • UP-REGULATION
  • FIBROBLASTS
  • CELLS

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