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

Poosti, F., Bansal, R., Yazdani, S., Prakash, J., Beljaars, L., van den Born, J., de Borst, M. H., Goor, van, H., Hillebrands, J-L. & Poelstra, K. 23-Aug-2016 In : Oncotarget. 7, 34, p. 54240-54252 13 p.

Research output: Scientific - peer-reviewArticle

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.

Original languageEnglish
Pages (from-to)54240-54252
Number of pages13
JournalOncotarget
Volume7
Issue number34
StatePublished - 23-Aug-2016

    Keywords

  • drug targeting, fibrosis, interferon gamma, kidney, myofibroblast, Pathology Section, CHRONIC KIDNEY-DISEASE, NUCLEAR-LOCALIZATION SEQUENCE, CD4(+) T-CELLS, IFN-GAMMA, TUBULOINTERSTITIAL FIBROSIS, MOLECULAR-MECHANISMS, VACCINIA VIRUS, GROWTH-FACTOR, FIBROBLASTS, LYMPHANGIOGENESIS

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