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Micellized Protein Transduction Domain-Bone Morphogenetic Protein-7 Efficiently Blocks Renal Fibrosis Via Inhibition of Transforming Growth Factor-Beta–Mediated Epithelial–Mesenchymal Transition

Authors
 Seonghun Kim  ;  Cheol-Hee Jeong  ;  Sang Hyun Song  ;  Jo Eun Um  ;  Hyun Sil Kim  ;  Jun Seop Yun  ;  Dawool Han  ;  Eunae Sandra Cho  ;  Bo Young Nam  ;  Jong In Yook  ;  Minhee Ku  ;  Jaemoon Yang  ;  Man-Deuk Kim  ;  Nam Hee Kim  ;  Tae-Hyun Yoo 
Citation
 FRONTIERS IN PHARMACOLOGY, Vol.11 : 591275, 2020-11 
Journal Title
 FRONTIERS IN PHARMACOLOGY 
Issue Date
2020-11
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.
Files in This Item:
T202005240.pdf Download
DOI
10.3389/fphar.2020.591275
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Oral Cancer Research Institute (구강종양연구소) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Ku, Min Hee(구민희) ORCID logo https://orcid.org/0000-0002-1674-1474
Kim, Nam Hee(김남희) ORCID logo https://orcid.org/0000-0002-3087-5276
Kim, Man Deuk(김만득) ORCID logo https://orcid.org/0000-0002-3575-5847
Kim, Hyun Sil(김현실) ORCID logo https://orcid.org/0000-0003-3614-1764
Yang, Jae Moon(양재문) ORCID logo https://orcid.org/0000-0001-7365-0395
Yoo, Tae Hyun(유태현) ORCID logo https://orcid.org/0000-0002-9183-4507
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Cho, Eunae(조은애산드라) ORCID logo https://orcid.org/0000-0002-0820-3019
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/180775
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