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

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

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2 Citations (Scopus)

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.

Original languageEnglish
Article number591275
JournalFrontiers in Pharmacology
Volume11
DOIs
Publication statusPublished - 2020 Nov 19

Bibliographical note

Funding Information:
We thank E. Tunkle for preparation of the manuscript. We also thank Joon Chae Na (Department of Urology, Yonsei University College of Medicine) for laparoscopic ureter ligation of pig UUO model.

Publisher Copyright:
© Copyright © 2020 Kim, Jeong, Song, Um, Kim, Yun, Han, Cho, Nam, Yook, Ku, Yang, Kim, Kim and Yoo.

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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