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THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial–Mesenchymal Transformation in Lipid Nephrotoxicity

Hyperlipidemia, an important risk factor for cardiovascular and end-stage renal diseases, often aggravates renal injury and compromises kidney function. Here, histological analysis of human kidney samples revealed that high lipid levels induced the development of renal fibrosis. To elucidate the mec...

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Autores principales: Gao, Li, Yang, Ting-ting, Zhang, Jun-sheng, Liu, Hong-xia, Cai, Dong-cheng, Wang, Lin-tao, Wang, Jing, Li, Xin-wei, Gao, Kun, Zhang, Su-ya, Cao, Yu-jia, Ji, Xiao-xia, Yang, Miao-miao, Han, Biao, Wang, Sheng, He, Lu, Nie, Xiao-yan, Liu, Dan-mei, Meng, Gang, He, Chao-yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930485/
https://www.ncbi.nlm.nih.gov/pubmed/33681182
http://dx.doi.org/10.3389/fcell.2020.601521
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author Gao, Li
Yang, Ting-ting
Zhang, Jun-sheng
Liu, Hong-xia
Cai, Dong-cheng
Wang, Lin-tao
Wang, Jing
Li, Xin-wei
Gao, Kun
Zhang, Su-ya
Cao, Yu-jia
Ji, Xiao-xia
Yang, Miao-miao
Han, Biao
Wang, Sheng
He, Lu
Nie, Xiao-yan
Liu, Dan-mei
Meng, Gang
He, Chao-yong
author_facet Gao, Li
Yang, Ting-ting
Zhang, Jun-sheng
Liu, Hong-xia
Cai, Dong-cheng
Wang, Lin-tao
Wang, Jing
Li, Xin-wei
Gao, Kun
Zhang, Su-ya
Cao, Yu-jia
Ji, Xiao-xia
Yang, Miao-miao
Han, Biao
Wang, Sheng
He, Lu
Nie, Xiao-yan
Liu, Dan-mei
Meng, Gang
He, Chao-yong
author_sort Gao, Li
collection PubMed
description Hyperlipidemia, an important risk factor for cardiovascular and end-stage renal diseases, often aggravates renal injury and compromises kidney function. Here, histological analysis of human kidney samples revealed that high lipid levels induced the development of renal fibrosis. To elucidate the mechanism underlying lipid nephrotoxicity, we used two types of mouse models (Apoe(−/−) and C57BL/6 mice fed a 45 and 60% high-fat diet, respectively). Histological analysis of kidney tissues revealed high-lipid-induced renal fibrosis and inflammation; this was confirmed by examining fibrotic and inflammatory marker expression using Western blotting and real-time polymerase chain reaction. Oxidized low-density lipoprotein (OX-LDL) significantly induced the fibrotic response in HK-2 tubular epithelial cells. RNA-sequencing and Gene Ontology analysis of differentially expressed mRNAs in OX-LDL-treated HK-2 tubular epithelial cells and real-time PCR validation in Apoe(−/−) mice showed that the expression of thrombospondin-1 (THBS1) in the high-fat group was significantly higher than that of the other top known genes, along with significant overexpression of its receptor CD47. THBS1 knockdown cells verified its relation to OX-LDL-induced fibrosis and inflammation. Liquid chromatography tandem mass spectrometry and STRING functional protein association network analyses predicted that THBS1/CD47 modulated the interaction between γ-catenin and E-cadherin and was involved in epithelial–mesenchymal transition, which was supported by immunoprecipitation and immunohistochemistry. CD47 downregulation following transfection with small-hairpin RNA in OX-LDL-treated tubular epithelial cells and treatment with anti-CD47 antibody restored the expression of E-cadherin and attenuated renal injury, fibrosis, and inflammatory response in OX-LDL-treated cells and in type 2 diabetes mellitus. These findings indicate that CD47 may serve as a potential therapeutic target in long-term lipid-induced kidney injury.
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spelling pubmed-79304852021-03-05 THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial–Mesenchymal Transformation in Lipid Nephrotoxicity Gao, Li Yang, Ting-ting Zhang, Jun-sheng Liu, Hong-xia Cai, Dong-cheng Wang, Lin-tao Wang, Jing Li, Xin-wei Gao, Kun Zhang, Su-ya Cao, Yu-jia Ji, Xiao-xia Yang, Miao-miao Han, Biao Wang, Sheng He, Lu Nie, Xiao-yan Liu, Dan-mei Meng, Gang He, Chao-yong Front Cell Dev Biol Cell and Developmental Biology Hyperlipidemia, an important risk factor for cardiovascular and end-stage renal diseases, often aggravates renal injury and compromises kidney function. Here, histological analysis of human kidney samples revealed that high lipid levels induced the development of renal fibrosis. To elucidate the mechanism underlying lipid nephrotoxicity, we used two types of mouse models (Apoe(−/−) and C57BL/6 mice fed a 45 and 60% high-fat diet, respectively). Histological analysis of kidney tissues revealed high-lipid-induced renal fibrosis and inflammation; this was confirmed by examining fibrotic and inflammatory marker expression using Western blotting and real-time polymerase chain reaction. Oxidized low-density lipoprotein (OX-LDL) significantly induced the fibrotic response in HK-2 tubular epithelial cells. RNA-sequencing and Gene Ontology analysis of differentially expressed mRNAs in OX-LDL-treated HK-2 tubular epithelial cells and real-time PCR validation in Apoe(−/−) mice showed that the expression of thrombospondin-1 (THBS1) in the high-fat group was significantly higher than that of the other top known genes, along with significant overexpression of its receptor CD47. THBS1 knockdown cells verified its relation to OX-LDL-induced fibrosis and inflammation. Liquid chromatography tandem mass spectrometry and STRING functional protein association network analyses predicted that THBS1/CD47 modulated the interaction between γ-catenin and E-cadherin and was involved in epithelial–mesenchymal transition, which was supported by immunoprecipitation and immunohistochemistry. CD47 downregulation following transfection with small-hairpin RNA in OX-LDL-treated tubular epithelial cells and treatment with anti-CD47 antibody restored the expression of E-cadherin and attenuated renal injury, fibrosis, and inflammatory response in OX-LDL-treated cells and in type 2 diabetes mellitus. These findings indicate that CD47 may serve as a potential therapeutic target in long-term lipid-induced kidney injury. Frontiers Media S.A. 2021-02-18 /pmc/articles/PMC7930485/ /pubmed/33681182 http://dx.doi.org/10.3389/fcell.2020.601521 Text en Copyright © 2021 Gao, Yang, Zhang, Liu, Cai, Wang, Wang, Li, Gao, Zhang, Cao, Ji, Yang, Han, Wang, He, Nie, Liu, Meng and He. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Gao, Li
Yang, Ting-ting
Zhang, Jun-sheng
Liu, Hong-xia
Cai, Dong-cheng
Wang, Lin-tao
Wang, Jing
Li, Xin-wei
Gao, Kun
Zhang, Su-ya
Cao, Yu-jia
Ji, Xiao-xia
Yang, Miao-miao
Han, Biao
Wang, Sheng
He, Lu
Nie, Xiao-yan
Liu, Dan-mei
Meng, Gang
He, Chao-yong
THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial–Mesenchymal Transformation in Lipid Nephrotoxicity
title THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial–Mesenchymal Transformation in Lipid Nephrotoxicity
title_full THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial–Mesenchymal Transformation in Lipid Nephrotoxicity
title_fullStr THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial–Mesenchymal Transformation in Lipid Nephrotoxicity
title_full_unstemmed THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial–Mesenchymal Transformation in Lipid Nephrotoxicity
title_short THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial–Mesenchymal Transformation in Lipid Nephrotoxicity
title_sort thbs1/cd47 modulates the interaction of γ-catenin with e-cadherin and participates in epithelial–mesenchymal transformation in lipid nephrotoxicity
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930485/
https://www.ncbi.nlm.nih.gov/pubmed/33681182
http://dx.doi.org/10.3389/fcell.2020.601521
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