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Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1

DNA methylation plays a pivotal role in the progression of renal fibrosis. Methyl-CpG–binding domain protein 2 (MBD2), a protein reader of methylation, is involved in the development of acute kidney injury (AKI) caused by vancomycin. However, the role and mechanism of action of MBD2 in renal remain...

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Autores principales: Ai, Kai, Li, Xiaozhou, Zhang, Pan, Pan, Jian, Li, Huiling, He, Zhibiao, Zhang, Hongliang, Yi, Lei, Kang, Ye, Wang, Yinhuai, Chen, Junxiang, Li, Yijian, Xiang, Xudong, Chai, Xiangping, Zhang, Dongshan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8933641/
https://www.ncbi.nlm.nih.gov/pubmed/35356685
http://dx.doi.org/10.1016/j.omtn.2022.02.015
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author Ai, Kai
Li, Xiaozhou
Zhang, Pan
Pan, Jian
Li, Huiling
He, Zhibiao
Zhang, Hongliang
Yi, Lei
Kang, Ye
Wang, Yinhuai
Chen, Junxiang
Li, Yijian
Xiang, Xudong
Chai, Xiangping
Zhang, Dongshan
author_facet Ai, Kai
Li, Xiaozhou
Zhang, Pan
Pan, Jian
Li, Huiling
He, Zhibiao
Zhang, Hongliang
Yi, Lei
Kang, Ye
Wang, Yinhuai
Chen, Junxiang
Li, Yijian
Xiang, Xudong
Chai, Xiangping
Zhang, Dongshan
author_sort Ai, Kai
collection PubMed
description DNA methylation plays a pivotal role in the progression of renal fibrosis. Methyl-CpG–binding domain protein 2 (MBD2), a protein reader of methylation, is involved in the development of acute kidney injury (AKI) caused by vancomycin. However, the role and mechanism of action of MBD2 in renal remain unclear. In this study, MBD2 mediated extracellular matrix (ECM) production induced by TGF-β1 in Boston University mouse proximal tubule (BUMPT) cells,and upregulated the expression EGR1 to promote ECM production in murine embryonic NIH 3T3 fibroblasts. ChIP analysis demonstrated that MBD2 physically interacted with the promoter region of the CpG islands of EGR1 genes and then activated their expression by inducing hypomethylation of the promoter region. In vivo, PT-MBD2-KO attenuated unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis via downregulation of EGR1, which was demonstrated by the downregulation of fibronectin (FN), collagen I and IV, α-SMA, and EGR1. Injection of MBD2-siRNA attenuated the UUO- and I/R-induced renal fibrosis. Those molecular changes were verified by biopsies from patients with obstructive nephropathy (OB). These data collectively demonstrated that inhibition of MBD2 reduces renal fibrosis via downregulating EGR1, which could be a target for treatment of fibrotic kidney disease.
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spelling pubmed-89336412022-03-29 Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1 Ai, Kai Li, Xiaozhou Zhang, Pan Pan, Jian Li, Huiling He, Zhibiao Zhang, Hongliang Yi, Lei Kang, Ye Wang, Yinhuai Chen, Junxiang Li, Yijian Xiang, Xudong Chai, Xiangping Zhang, Dongshan Mol Ther Nucleic Acids Original Article DNA methylation plays a pivotal role in the progression of renal fibrosis. Methyl-CpG–binding domain protein 2 (MBD2), a protein reader of methylation, is involved in the development of acute kidney injury (AKI) caused by vancomycin. However, the role and mechanism of action of MBD2 in renal remain unclear. In this study, MBD2 mediated extracellular matrix (ECM) production induced by TGF-β1 in Boston University mouse proximal tubule (BUMPT) cells,and upregulated the expression EGR1 to promote ECM production in murine embryonic NIH 3T3 fibroblasts. ChIP analysis demonstrated that MBD2 physically interacted with the promoter region of the CpG islands of EGR1 genes and then activated their expression by inducing hypomethylation of the promoter region. In vivo, PT-MBD2-KO attenuated unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis via downregulation of EGR1, which was demonstrated by the downregulation of fibronectin (FN), collagen I and IV, α-SMA, and EGR1. Injection of MBD2-siRNA attenuated the UUO- and I/R-induced renal fibrosis. Those molecular changes were verified by biopsies from patients with obstructive nephropathy (OB). These data collectively demonstrated that inhibition of MBD2 reduces renal fibrosis via downregulating EGR1, which could be a target for treatment of fibrotic kidney disease. American Society of Gene & Cell Therapy 2022-02-28 /pmc/articles/PMC8933641/ /pubmed/35356685 http://dx.doi.org/10.1016/j.omtn.2022.02.015 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Ai, Kai
Li, Xiaozhou
Zhang, Pan
Pan, Jian
Li, Huiling
He, Zhibiao
Zhang, Hongliang
Yi, Lei
Kang, Ye
Wang, Yinhuai
Chen, Junxiang
Li, Yijian
Xiang, Xudong
Chai, Xiangping
Zhang, Dongshan
Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1
title Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1
title_full Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1
title_fullStr Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1
title_full_unstemmed Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1
title_short Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1
title_sort genetic or sirna inhibition of mbd2 attenuates the uuo- and i/r-induced renal fibrosis via downregulation of egr1
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8933641/
https://www.ncbi.nlm.nih.gov/pubmed/35356685
http://dx.doi.org/10.1016/j.omtn.2022.02.015
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