Oncotarget

Research Papers: Pathology:

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

Fariba Poosti _, Ruchi Bansal, Saleh Yazdani, Jai Prakash, Leonie Beljaars, Jacob van den Born, Martin H. de Borst, Harry van Goor, Jan-Luuk Hillebrands and Klaas Poelstra

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Oncotarget. 2016; 7:54240-54252. https://doi.org/10.18632/oncotarget.11095

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Abstract

Fariba Poosti1,5, Ruchi Bansal2, Saleh Yazdani2, Jai Prakash2, Leonie Beljaars3, Jacob van den Born4, Martin H. de Borst4, Harry van Goor1, Jan-Luuk Hillebrands1,* and Klaas Poelstra3,*

1 Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

2 Department of Biomaterials Science and Technology, Division of Targeted Therapeutics, MIRA Institute, University of Twente, Enschede, The Netherlands

3 Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands

4 Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

5 Department of Microbiology and Immunology, Laboratory of Molecular Immunology, Rega Institute, KU Leuven, Belgium

* Share senior authorship

Correspondence to:

Jan-Luuk Hillebrands, email:

Keywords: drug targeting, fibrosis, interferon gamma, kidney, myofibroblast, Pathology Section

Received: March 07, 2016 Accepted: June 20, 2016 Published: August 05, 2016

Abstract

Renal fibrosis cannot be adequately treated since anti-fibrotic treatment is lacking. Interferon-γ is a pro-inflammatory cytokine with anti-fibrotic properties. Clinical use of interferon-γ is hampered due to inflammation-mediated systemic side effects. We used an interferon-γ peptidomimetic (mimγ) lacking the extracellular IFNγReceptor recognition domain, and coupled it to the PDGFβR-recognizing peptide BiPPB. Here we tested the efficacy of mimγ-BiPPB (referred to as “Fibroferon”) targeted to PDGFβR-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 α-SMA, TGFβ1, fibronectin, and collagens I and III protein and/or mRNA expression. Fibroferon treatment significantly reduced expression of these fibrotic markers. Compared to full-length IFNγ, anti-fibrotic effects of Fibroferon were more pronounced. Unilateral ureter obstruction-induced lymphangiogenesis was significantly reduced by Fibroferon but not full-length IFNγ. In contrast to full-length IFNγ, Fibroferon did not induce IFNγ-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 IFNγ, the IFNγ-peptidomimetic Fibroferon targeted to PDGFβR-overexpressing myofibroblasts attenuates renal fibrosis in the absence of IFNγ-mediated adverse effects.


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