Interferon gamma peptidomimetic targeted to interstitial myofibroblasts attenuates renal fibrosis after unilateral ureteral obstruction in mice

Renal fibrosis cannot be adequately treated since anti-fibrotic treatment is lacking. Interferon-gamma is a pro-inflammatory cytokine with anti-fibrotic properties. Clinical use of interferon-gamma is hampered due to inflammation-mediated systemic side effects. We used an interferon-gamma peptidomimetic (mim gamma) lacking the extracellular IFN gamma Receptor recognition domain, and coupled it to the PDGF beta R-recognizing peptide BiPPB. Here we tested the efficacy of mim gamma-BiPPB (referred to as "Fibroferon") targeted to PDGF beta R-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 alpha-SMA, TGF beta 1, fibronectin, and collagens I and III protein and/or mRNA expression. Fibroferon treatment significantly reduced expression of these fibrotic markers. Compared to full-length IFN gamma, anti-fibrotic effects of Fibroferon were more pronounced. Unilateral ureter obstruction-induced lymphangiogenesis was significantly reduced by Fibroferon but not full-length IFN gamma. In contrast to full-length IFN gamma, Fibroferon did not induce IFN gamma-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 IFN gamma, the IFN gamma-peptidomimetic Fibroferon targeted to PDGF beta R-overexpressing myofibroblasts attenuates renal fibrosis in the absence of IFN gamma-mediated adverse effects.