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Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis

Progressive glomerulonephritis (GN) is characterized by an excessive accumulation of extracellular (ECM) proteins, mainly type IV collagen (COLIV), in the glomerulus leading to glomerulosclerosis. The current therapeutic approach to GN is suboptimal. Epigenetic drugs could be novel therapeutic optio...

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Autores principales: Morgado-Pascual, José Luis, Suarez-Alvarez, Beatriz, Marchant, Vanessa, Basantes, Pamela, Tharaux, Pierre-Louis, Ortiz, Alberto, Lopez-Larrea, Carlos, Ruiz-Ortega, Marta, Rayego-Mateos, Sandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820124/
https://www.ncbi.nlm.nih.gov/pubmed/36613933
http://dx.doi.org/10.3390/ijms24010486
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author Morgado-Pascual, José Luis
Suarez-Alvarez, Beatriz
Marchant, Vanessa
Basantes, Pamela
Tharaux, Pierre-Louis
Ortiz, Alberto
Lopez-Larrea, Carlos
Ruiz-Ortega, Marta
Rayego-Mateos, Sandra
author_facet Morgado-Pascual, José Luis
Suarez-Alvarez, Beatriz
Marchant, Vanessa
Basantes, Pamela
Tharaux, Pierre-Louis
Ortiz, Alberto
Lopez-Larrea, Carlos
Ruiz-Ortega, Marta
Rayego-Mateos, Sandra
author_sort Morgado-Pascual, José Luis
collection PubMed
description Progressive glomerulonephritis (GN) is characterized by an excessive accumulation of extracellular (ECM) proteins, mainly type IV collagen (COLIV), in the glomerulus leading to glomerulosclerosis. The current therapeutic approach to GN is suboptimal. Epigenetic drugs could be novel therapeutic options for human disease. Among these drugs, bromodomain and extra-terminal domain (BET) inhibitors (iBETs) have shown beneficial effects in experimental kidney disease and fibrotic disorders. Sex-determining region Y-box 9 (SOX9) is a transcription factor involved in regulating proliferation, migration, and regeneration, but its role in kidney fibrosis is still unclear. We investigated whether iBETs could regulate ECM accumulation in experimental GN and evaluated the role of SOX9 in this process. For this purpose, we tested the iBET JQ1 in mice with anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS). In NTS-injected mice, JQ1 treatment reduced glomerular ECM deposition, mainly by inhibiting glomerular COLIV accumulation and Col4a3 gene overexpression. Moreover, chromatin immunoprecipitation assays demonstrated that JQ1 inhibited the recruitment and binding of BRD4 to the Col4a3 promoter and reduced its transcription. Active SOX9 was found in the nuclei of glomerular cells of NTS-injured kidneys, mainly in COLIV-stained regions. JQ1 treatment blocked SOX9 nuclear translocation in injured kidneys. Moreover, in vitro JQ1 blocked TGF-β1-induced SOX9 activation and ECM production in cultured mesangial cells. Additionally, SOX9 gene silencing inhibited ECM production, including COLIV production. Our results demonstrated that JQ1 inhibited SOX9/COLIV, to reduce experimental glomerulosclerosis, supporting further research of iBET as a potential therapeutic option in progressive glomerulosclerosis.
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spelling pubmed-98201242023-01-07 Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis Morgado-Pascual, José Luis Suarez-Alvarez, Beatriz Marchant, Vanessa Basantes, Pamela Tharaux, Pierre-Louis Ortiz, Alberto Lopez-Larrea, Carlos Ruiz-Ortega, Marta Rayego-Mateos, Sandra Int J Mol Sci Article Progressive glomerulonephritis (GN) is characterized by an excessive accumulation of extracellular (ECM) proteins, mainly type IV collagen (COLIV), in the glomerulus leading to glomerulosclerosis. The current therapeutic approach to GN is suboptimal. Epigenetic drugs could be novel therapeutic options for human disease. Among these drugs, bromodomain and extra-terminal domain (BET) inhibitors (iBETs) have shown beneficial effects in experimental kidney disease and fibrotic disorders. Sex-determining region Y-box 9 (SOX9) is a transcription factor involved in regulating proliferation, migration, and regeneration, but its role in kidney fibrosis is still unclear. We investigated whether iBETs could regulate ECM accumulation in experimental GN and evaluated the role of SOX9 in this process. For this purpose, we tested the iBET JQ1 in mice with anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS). In NTS-injected mice, JQ1 treatment reduced glomerular ECM deposition, mainly by inhibiting glomerular COLIV accumulation and Col4a3 gene overexpression. Moreover, chromatin immunoprecipitation assays demonstrated that JQ1 inhibited the recruitment and binding of BRD4 to the Col4a3 promoter and reduced its transcription. Active SOX9 was found in the nuclei of glomerular cells of NTS-injured kidneys, mainly in COLIV-stained regions. JQ1 treatment blocked SOX9 nuclear translocation in injured kidneys. Moreover, in vitro JQ1 blocked TGF-β1-induced SOX9 activation and ECM production in cultured mesangial cells. Additionally, SOX9 gene silencing inhibited ECM production, including COLIV production. Our results demonstrated that JQ1 inhibited SOX9/COLIV, to reduce experimental glomerulosclerosis, supporting further research of iBET as a potential therapeutic option in progressive glomerulosclerosis. MDPI 2022-12-28 /pmc/articles/PMC9820124/ /pubmed/36613933 http://dx.doi.org/10.3390/ijms24010486 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
Morgado-Pascual, José Luis
Suarez-Alvarez, Beatriz
Marchant, Vanessa
Basantes, Pamela
Tharaux, Pierre-Louis
Ortiz, Alberto
Lopez-Larrea, Carlos
Ruiz-Ortega, Marta
Rayego-Mateos, Sandra
Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis
title Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis
title_full Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis
title_fullStr Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis
title_full_unstemmed Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis
title_short Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis
title_sort type iv collagen and sox9 are molecular targets of bet inhibition in experimental glomerulosclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820124/
https://www.ncbi.nlm.nih.gov/pubmed/36613933
http://dx.doi.org/10.3390/ijms24010486
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