Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Takano, Mei, Toda, Shota, Watanabe, Hiroshi, Fujimura, Rui, Nishida, Kento, Bi, Jing, Minayoshi, Yuki, Miyahisa, Masako, Maeda, Hitoshi, Maruyama, Toru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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
_version_ 1784754899891781632
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
work_keys_str_mv AT takanomei engineeringofalongactingbonemorphogeneticprotein7byfusionwithalbuminforthetreatmentofrenalinjury
AT todashota engineeringofalongactingbonemorphogeneticprotein7byfusionwithalbuminforthetreatmentofrenalinjury
AT watanabehiroshi engineeringofalongactingbonemorphogeneticprotein7byfusionwithalbuminforthetreatmentofrenalinjury
AT fujimurarui engineeringofalongactingbonemorphogeneticprotein7byfusionwithalbuminforthetreatmentofrenalinjury
AT nishidakento engineeringofalongactingbonemorphogeneticprotein7byfusionwithalbuminforthetreatmentofrenalinjury
AT bijing engineeringofalongactingbonemorphogeneticprotein7byfusionwithalbuminforthetreatmentofrenalinjury
AT minayoshiyuki engineeringofalongactingbonemorphogeneticprotein7byfusionwithalbuminforthetreatmentofrenalinjury
AT miyahisamasako engineeringofalongactingbonemorphogeneticprotein7byfusionwithalbuminforthetreatmentofrenalinjury
AT maedahitoshi engineeringofalongactingbonemorphogeneticprotein7byfusionwithalbuminforthetreatmentofrenalinjury
AT maruyamatoru engineeringofalongactingbonemorphogeneticprotein7byfusionwithalbuminforthetreatmentofrenalinjury