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- Title
Selective delivery of IFN-γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis.
- Authors
Poosti, Fariba; Bansal, Ruchi; Yazdani, Saleh; Prakash, Jai; Post, Eduard; Klok, Pieter; den Born, Jacob van; de Borst, Martin H.; van Goor, Harry; Poelstra, Klaas; Hillebrands, Jan-Luuk
- 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 (PDGFRb)-expressing myofibroblasts attenuates fibrosis in an obstructive ne-phropathy [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. PDGFRb expression was > 3-fold increased (P < 0.05) in mouse fibrotic UUO kidneys and colocalized with a-smooth muscle actin-positive (SMA+) myofibroblasts. In vitro, PPB-PEG-IFN-γ significantly inhibited col1a1, col1a2, and α-SMA mRNA expression in TGF-b-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 lymphangio-genesis (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 PDGFRb-expressing myofibroblasts attenuates renal fibrosis and reduces systemic adverse effects.
- Subjects
MYOFIBROBLASTS; RENAL fibrosis; CYTOKINES; KIDNEY diseases; EXPERIMENTAL biology
- Publication
FASEB Journal, 2015, Vol 29, Issue 3, p1029
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.14-258459