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Engineering of a Long-Acting Bone Morphogenetic Protein-7 by Fusion with Albumin for the Treatment of Renal Injury
The bone morphogenetic protein-7 (BMP7) is capable of inhibiting TGF-β/Smad3 signaling, which subsequently results in protecting the kidney from renal fibrosis, but its lower blood retention and osteogenic activity are bottlenecks for its clinical application. We report herein on the fusion of carbo...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316787/ https://www.ncbi.nlm.nih.gov/pubmed/35890230 http://dx.doi.org/10.3390/pharmaceutics14071334 |
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author | Takano, Mei Toda, Shota Watanabe, Hiroshi Fujimura, Rui Nishida, Kento Bi, Jing Minayoshi, Yuki Miyahisa, Masako Maeda, Hitoshi Maruyama, Toru |
author_facet | Takano, Mei Toda, Shota Watanabe, Hiroshi Fujimura, Rui Nishida, Kento Bi, Jing Minayoshi, Yuki Miyahisa, Masako Maeda, Hitoshi Maruyama, Toru |
author_sort | Takano, Mei |
collection | PubMed |
description | The bone morphogenetic protein-7 (BMP7) is capable of inhibiting TGF-β/Smad3 signaling, which subsequently results in protecting the kidney from renal fibrosis, but its lower blood retention and osteogenic activity are bottlenecks for its clinical application. We report herein on the fusion of carbohydrate-deficient human BMP7 and human serum albumin (HSA-BMP7) using albumin fusion technology and site-directed mutagenesis. When using mouse myoblast cells, no osteogenesis was observed in the glycosylated BMP7 derived from Chinese hamster ovary cells in the case of unglycosylated BMP7 derived from Escherichia coli and HSA-BMP7. On the contrary, the specific activity for the Smad1/5/8 phosphorylation of HSA-BMP7 was about 25~50-times lower than that for the glycosylated BMP7, but the phosphorylation activity of the HSA-BMP7 was retained. A pharmacokinetic profile showed that the plasma half-life of HSA-BMP7 was similar to that for HSA and was nearly 10 times longer than that of BMP7. In unilateral ureteral obstruction mice, weekly dosing of HSA-BMP7 significantly attenuated renal fibrosis, but the individual components, i.e., HSA or BMP7, did not. HSA-BMP7 also attenuated a cisplatin-induced acute kidney dysfunction model. The findings reported herein indicate that HSA-BMP7 has the potential for use in clinical applications for the treatment of renal injuries. |
format | Online Article Text |
id | pubmed-9316787 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93167872022-07-27 Engineering of a Long-Acting Bone Morphogenetic Protein-7 by Fusion with Albumin for the Treatment of Renal Injury Takano, Mei Toda, Shota Watanabe, Hiroshi Fujimura, Rui Nishida, Kento Bi, Jing Minayoshi, Yuki Miyahisa, Masako Maeda, Hitoshi Maruyama, Toru Pharmaceutics Article The bone morphogenetic protein-7 (BMP7) is capable of inhibiting TGF-β/Smad3 signaling, which subsequently results in protecting the kidney from renal fibrosis, but its lower blood retention and osteogenic activity are bottlenecks for its clinical application. We report herein on the fusion of carbohydrate-deficient human BMP7 and human serum albumin (HSA-BMP7) using albumin fusion technology and site-directed mutagenesis. When using mouse myoblast cells, no osteogenesis was observed in the glycosylated BMP7 derived from Chinese hamster ovary cells in the case of unglycosylated BMP7 derived from Escherichia coli and HSA-BMP7. On the contrary, the specific activity for the Smad1/5/8 phosphorylation of HSA-BMP7 was about 25~50-times lower than that for the glycosylated BMP7, but the phosphorylation activity of the HSA-BMP7 was retained. A pharmacokinetic profile showed that the plasma half-life of HSA-BMP7 was similar to that for HSA and was nearly 10 times longer than that of BMP7. In unilateral ureteral obstruction mice, weekly dosing of HSA-BMP7 significantly attenuated renal fibrosis, but the individual components, i.e., HSA or BMP7, did not. HSA-BMP7 also attenuated a cisplatin-induced acute kidney dysfunction model. The findings reported herein indicate that HSA-BMP7 has the potential for use in clinical applications for the treatment of renal injuries. MDPI 2022-06-24 /pmc/articles/PMC9316787/ /pubmed/35890230 http://dx.doi.org/10.3390/pharmaceutics14071334 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Takano, Mei Toda, Shota Watanabe, Hiroshi Fujimura, Rui Nishida, Kento Bi, Jing Minayoshi, Yuki Miyahisa, Masako Maeda, Hitoshi Maruyama, Toru Engineering of a Long-Acting Bone Morphogenetic Protein-7 by Fusion with Albumin for the Treatment of Renal Injury |
title | Engineering of a Long-Acting Bone Morphogenetic Protein-7 by Fusion with Albumin for the Treatment of Renal Injury |
title_full | Engineering of a Long-Acting Bone Morphogenetic Protein-7 by Fusion with Albumin for the Treatment of Renal Injury |
title_fullStr | Engineering of a Long-Acting Bone Morphogenetic Protein-7 by Fusion with Albumin for the Treatment of Renal Injury |
title_full_unstemmed | Engineering of a Long-Acting Bone Morphogenetic Protein-7 by Fusion with Albumin for the Treatment of Renal Injury |
title_short | Engineering of a Long-Acting Bone Morphogenetic Protein-7 by Fusion with Albumin for the Treatment of Renal Injury |
title_sort | engineering of a long-acting bone morphogenetic protein-7 by fusion with albumin for the treatment of renal injury |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316787/ https://www.ncbi.nlm.nih.gov/pubmed/35890230 http://dx.doi.org/10.3390/pharmaceutics14071334 |
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