AUTHOR=Kim Seonghun , Jeong Cheol-Hee , Song Sang Hyun , Um Jo Eun , Kim Hyun Sil , Yun Jun Seop , Han Dawool , Cho Eunae Sandra , Nam Bo Young , Yook Jong In , Ku Minhee , Yang Jaemoon , Kim Man-Deuk , Kim Nam Hee , Yoo Tae-Hyun TITLE=Micellized Protein Transduction Domain-Bone Morphogenetic Protein-7 Efficiently Blocks Renal Fibrosis Via Inhibition of Transforming Growth Factor-Beta–Mediated Epithelial–Mesenchymal Transition JOURNAL=Frontiers in Pharmacology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.591275 DOI=10.3389/fphar.2020.591275 ISSN=1663-9812 ABSTRACT=

Tubulointerstitial renal fibrosis is a chronic disease process affecting chronic kidney disease (CKD). While the etiological role of transforming growth factor-beta (TGF-β) is well known for epithelial–mesenchymal transition (EMT) in chronic kidney disease, effective therapeutics for renal fibrosis are largely limited. As a member of the TGF-β superfamily, bone morphogenetic protein-7 (BMP-7) plays an important role as an endogenous antagonist of TGF-β, inhibiting fibrotic progression in many organs. However, soluble rhBMP-7 is hardly available for therapeutics due to its limited pharmacodynamic profile and rapid clearance in clinical settings. In this study, we have developed a novel therapeutic approach with protein transduction domain (PTD) fused BMP-7 in micelle (mPTD-BMP-7) for long-range signaling in vivo. Contrary to rhBMP-7 targeting its cognate receptors, the nano-sized mPTD-BMP-7 is transduced into cells through an endosomal pathway and secreted to the exosome having active BMP-7. Further, transduced mPTD-BMP-7 successfully activates SMAD1/5/8 and inhibits the TGF-β–mediated epithelial–mesenchymal transition process in vitro and in an in vivo unilateral ureter obstruction model. To determine the clinical relevance of our strategy, we also developed an intra-arterial administration of mPTD-BMP-7 through renal artery in pigs. Interestingly, mPTD-BMP-7 through renal artery intervention effectively delivered into Bowman’s space and inhibits unilateral ureter obstruction–induced renal fibrosis in pigs. Our results provide a novel therapeutic targeting TGF-β–mediated renal fibrosis and other organs as well as a clinically available approach for kidney.