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

Renal fibrosis leads to end-stage renal disease demanding renal replacement therapy because no adequate treatment exists. IFN-gamma is an antifibrotic cytokine that may attenuate renal fibrosis. Systemically administered IFN-gamma 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-gamma to platelet-derived growth factor receptor beta (PDGFR beta)-expressing myofibroblasts attenuates fibrosis in an obstructive nephropathy [unilateral ureteral obstruction (UUO)] mouse model. PEGylated IFN-gamma conjugated to PDGFR beta-recognizing peptide [(PPB)-polyethylene glycol (PEG)-IFN-gamma] was tested in vitro and in vivo for antifibrotic properties and compared with free IFN-gamma. PDGFR beta expression was >3-fold increased (P < 0.05) in mouse fibrotic UUO kidneys and colocalized with alpha-smooth muscle actin-positive (SMA(+)) myofibroblasts. In vitro, PPB-PEG-IFN-gamma significantly inhibited colla1, colla2, and alpha-SMA mRNA expression in TGF-beta-activated NIH3T3 fibroblasts (P < 0.05). In vivo, PPB-PEG-IFN-g gamma specifically accumulated in PDGFR beta-positive myofibroblasts. PPB-PEG-IFN-gamma treatment significantly reduced renal collagen I, fibronectin, and alpha-SMA mRNA and protein expression. Compared with vehicle treatment, PPB-PEG-IFN-gamma preserved tubular morphology, reduced interstitial T-cell infiltration, and attenuated lymphangiogenesis (all P < 0.05) without affecting peritubular capillary density. PPB-PEG-IFN-gamma reducedIFN-gamma-related side effects as manifested by reducedmajor histocompatibility complex class II expression in brain tissue (P < 0.05 vs. free IFN-gamma). Our findings demonstrate that specific targeting of IFN-gamma to PDGFR-beta-expressing myofibroblasts attenuates renal fibrosis and reduces systemic adverse effects.