Newly designed Protein Transduction Domain (PTD)-mediated BMP-7 is a potential therapeutic for peritoneal fibrosis.

While the bone morphogenetic protein-7 (BMP-7) is a well-known therapeutic growth factor reverting many fibrotic diseases, including peritoneal fibrosis by peritoneal dialysis (PD), soluble growth factors are largely limited in clinical applications owing to their short half-life in clinical settings. Recently, we developed a novel drug delivery model using protein transduction domains (PTD) overcoming limitation of soluble recombinant proteins, including bone morphogenetic protein-7 (BMP-7). This study aims at evaluating the therapeutic effects of PTD-BMP-7 consisted of PTD and full-length BMP-7 on epithelial-mesenchymal transition (EMT)-related fibrosis. Human peritoneal mesothelial cells (HPMCs) were then treated with TGF-β1 or TGF-β1 + PTD-BMP-7. Peritoneal dialysis (PD) catheters were inserted into Sprague-Dawley rats, and these rats were infused intra-peritoneally with saline, peritoneal dialysis fluid (PDF) or PDF + PTD-BMP-7. In vitro, TGF-β1 treatment significantly increased fibronectin, type I collagen, α-SMA and Snail expression, while reducing E-cadherin expression in HPMCs (P < .001). PTD-BMP-7 treatment ameliorated TGF-β1-induced fibronectin, type I collagen, α-SMA and Snail expression, and restored E-cadherin expression in HPMCs (P < .001). In vivo, the expressions of EMT-related molecules and the thickness of the sub-mesothelial layer were significantly increased in the peritoneum of rats treated with PDF, and these changes were significantly abrogated by the intra-peritoneal administration of PTD-BMP-7. PTD-BMP-7 treatment significantly inhibited the progression of established PD fibrosis. These findings suggest that PTD-BMP-7, as a prodrug of BMP-7, can be an effective therapeutic agent for peritoneal fibrosis in PD patients. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Citation

Seonghun Kim, Dong Ho Shin, Bo Young Nam, Hye-Young Kang, Jimin Park, Meiyan Wu, Nam Hee Kim, Hyun Sil Kim, Jung Tak Park, Seung Hyeok Han, Shin-Wook Kang, Jong In Yook, Tae-Hyun Yoo. Newly designed Protein Transduction Domain (PTD)-mediated BMP-7 is a potential therapeutic for peritoneal fibrosis. Journal of cellular and molecular medicine. 2020 Nov;24(22):13507-13522

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PMID: 33079436

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