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

ABSTRACT: Tubulointerstitial renal fibrosis is a chronic disease process affecting chronic kidney disease (CKD). While the etiological role of transforming growth factor-beta (TGF-?) 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-? superfamily, bone morphogenetic protein-7 (BMP-7) plays an important role as an endogenous antagonist of TGF-?, 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-?-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-?-mediated renal fibrosis and other organs as well as a clinically available approach for kidney.

SUBMITTER: Kim S 

PROVIDER: S-EPMC7751754 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature