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Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis

BACKGROUND: Upregulation of an RNA-binding protein HuR has been implicated in glomerular diseases. Herein, we evaluated whether it is involved in renal tubular fibrosis. METHODS: HuR was firstly examined in human kidney biopsy tissue with tubular disease. Second, its expression and the effect of HuR...

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Autores principales: Huang, Zhimin, Liu, Simeng, Tang, Anna, Wu, Xiaoqing, Aube, Jeffrey, Xu, Liang, Huang, Yufeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10311833/
https://www.ncbi.nlm.nih.gov/pubmed/37391777
http://dx.doi.org/10.1186/s12967-023-04298-x
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author Huang, Zhimin
Liu, Simeng
Tang, Anna
Wu, Xiaoqing
Aube, Jeffrey
Xu, Liang
Huang, Yufeng
author_facet Huang, Zhimin
Liu, Simeng
Tang, Anna
Wu, Xiaoqing
Aube, Jeffrey
Xu, Liang
Huang, Yufeng
author_sort Huang, Zhimin
collection PubMed
description BACKGROUND: Upregulation of an RNA-binding protein HuR has been implicated in glomerular diseases. Herein, we evaluated whether it is involved in renal tubular fibrosis. METHODS: HuR was firstly examined in human kidney biopsy tissue with tubular disease. Second, its expression and the effect of HuR inhibition with KH3 on tubular injury were further assessed in a mouse model induced by a unilateral renal ischemia/reperfusion (IR). KH3 (50 mg kg(−1)) was given daily via intraperitoneal injection from day 3 to 14 after IR. Last, one of HuR-targeted pathways was examined in cultured proximal tubular cells. RESULTS: HuR significantly increases at the site of tubular injury both in progressive CKD in patients and in IR-injured kidneys in mice, accompanied by upregulation of HuR targets that are involved in inflammation, profibrotic cytokines, oxidative stress, proliferation, apoptosis, tubular EMT process, matrix remodeling and fibrosis in renal tubulointerstitial fibrosis. KH3 treatment reduces the IR-induced tubular injury and fibrosis, accompanied by the remarkable amelioration in those involved pathways. A panel of mRNA array further revealed that 519 molecules in mouse kidney following IR injury changed their expression and 71.3% of them that are involved in 50 profibrotic pathways, were ameliorated when treated with KH3. In vitro, TGFβ1 induced tubular HuR cytoplasmic translocation and subsequent tubular EMT, which were abrogated by KH3 administration in cultured HK-2 cells. CONCLUSIONS: These results suggest that excessive upregulation of HuR contributes to renal tubulointerstitial fibrosis by dysregulating genes involved in multiple profibrotic pathways and activating the TGFß1/HuR feedback circuit in tubular cells. Inhibition of HuR may have therapeutic potential for renal tubular fibrosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04298-x.
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spelling pubmed-103118332023-07-01 Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis Huang, Zhimin Liu, Simeng Tang, Anna Wu, Xiaoqing Aube, Jeffrey Xu, Liang Huang, Yufeng J Transl Med Research BACKGROUND: Upregulation of an RNA-binding protein HuR has been implicated in glomerular diseases. Herein, we evaluated whether it is involved in renal tubular fibrosis. METHODS: HuR was firstly examined in human kidney biopsy tissue with tubular disease. Second, its expression and the effect of HuR inhibition with KH3 on tubular injury were further assessed in a mouse model induced by a unilateral renal ischemia/reperfusion (IR). KH3 (50 mg kg(−1)) was given daily via intraperitoneal injection from day 3 to 14 after IR. Last, one of HuR-targeted pathways was examined in cultured proximal tubular cells. RESULTS: HuR significantly increases at the site of tubular injury both in progressive CKD in patients and in IR-injured kidneys in mice, accompanied by upregulation of HuR targets that are involved in inflammation, profibrotic cytokines, oxidative stress, proliferation, apoptosis, tubular EMT process, matrix remodeling and fibrosis in renal tubulointerstitial fibrosis. KH3 treatment reduces the IR-induced tubular injury and fibrosis, accompanied by the remarkable amelioration in those involved pathways. A panel of mRNA array further revealed that 519 molecules in mouse kidney following IR injury changed their expression and 71.3% of them that are involved in 50 profibrotic pathways, were ameliorated when treated with KH3. In vitro, TGFβ1 induced tubular HuR cytoplasmic translocation and subsequent tubular EMT, which were abrogated by KH3 administration in cultured HK-2 cells. CONCLUSIONS: These results suggest that excessive upregulation of HuR contributes to renal tubulointerstitial fibrosis by dysregulating genes involved in multiple profibrotic pathways and activating the TGFß1/HuR feedback circuit in tubular cells. Inhibition of HuR may have therapeutic potential for renal tubular fibrosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04298-x. BioMed Central 2023-06-30 /pmc/articles/PMC10311833/ /pubmed/37391777 http://dx.doi.org/10.1186/s12967-023-04298-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Huang, Zhimin
Liu, Simeng
Tang, Anna
Wu, Xiaoqing
Aube, Jeffrey
Xu, Liang
Huang, Yufeng
Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis
title Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis
title_full Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis
title_fullStr Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis
title_full_unstemmed Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis
title_short Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis
title_sort targeting rna-binding protein hur to inhibit the progression of renal tubular fibrosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10311833/
https://www.ncbi.nlm.nih.gov/pubmed/37391777
http://dx.doi.org/10.1186/s12967-023-04298-x
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