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Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis

Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treatment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provides limited efficacy and an important burden of adverse events. Epigenetic drugs are a sourc...

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Autores principales: Tejedor-Santamaria, Lucia, Morgado-Pascual, Jose Luis, Marquez-Exposito, Laura, Suarez-Alvarez, Beatriz, Rodrigues-Diez, Raul R., Tejera-Muñoz, Antonio, Marchant, Vanessa, Mezzano, Sergio, Lopez-Larrea, Carlos, Sola, Anna, Fernandez-Juarez, Gema Maria, Ortiz, Alberto, Rayego-Mateos, Sandra, Ruiz-Ortega, Marta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876310/
https://www.ncbi.nlm.nih.gov/pubmed/35215234
http://dx.doi.org/10.3390/ph15020121
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author Tejedor-Santamaria, Lucia
Morgado-Pascual, Jose Luis
Marquez-Exposito, Laura
Suarez-Alvarez, Beatriz
Rodrigues-Diez, Raul R.
Tejera-Muñoz, Antonio
Marchant, Vanessa
Mezzano, Sergio
Lopez-Larrea, Carlos
Sola, Anna
Fernandez-Juarez, Gema Maria
Ortiz, Alberto
Rayego-Mateos, Sandra
Ruiz-Ortega, Marta
author_facet Tejedor-Santamaria, Lucia
Morgado-Pascual, Jose Luis
Marquez-Exposito, Laura
Suarez-Alvarez, Beatriz
Rodrigues-Diez, Raul R.
Tejera-Muñoz, Antonio
Marchant, Vanessa
Mezzano, Sergio
Lopez-Larrea, Carlos
Sola, Anna
Fernandez-Juarez, Gema Maria
Ortiz, Alberto
Rayego-Mateos, Sandra
Ruiz-Ortega, Marta
author_sort Tejedor-Santamaria, Lucia
collection PubMed
description Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treatment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provides limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory disorders and experimental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs could regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model resembling human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, restoring podocyte numbers. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by modulation of NOTCH pathway. JQ1 inhibited the gene expression of the NOTCH effectors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis.
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spelling pubmed-88763102022-02-26 Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis Tejedor-Santamaria, Lucia Morgado-Pascual, Jose Luis Marquez-Exposito, Laura Suarez-Alvarez, Beatriz Rodrigues-Diez, Raul R. Tejera-Muñoz, Antonio Marchant, Vanessa Mezzano, Sergio Lopez-Larrea, Carlos Sola, Anna Fernandez-Juarez, Gema Maria Ortiz, Alberto Rayego-Mateos, Sandra Ruiz-Ortega, Marta Pharmaceuticals (Basel) Article Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treatment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provides limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory disorders and experimental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs could regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model resembling human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, restoring podocyte numbers. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by modulation of NOTCH pathway. JQ1 inhibited the gene expression of the NOTCH effectors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis. MDPI 2022-01-20 /pmc/articles/PMC8876310/ /pubmed/35215234 http://dx.doi.org/10.3390/ph15020121 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
Tejedor-Santamaria, Lucia
Morgado-Pascual, Jose Luis
Marquez-Exposito, Laura
Suarez-Alvarez, Beatriz
Rodrigues-Diez, Raul R.
Tejera-Muñoz, Antonio
Marchant, Vanessa
Mezzano, Sergio
Lopez-Larrea, Carlos
Sola, Anna
Fernandez-Juarez, Gema Maria
Ortiz, Alberto
Rayego-Mateos, Sandra
Ruiz-Ortega, Marta
Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis
title Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis
title_full Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis
title_fullStr Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis
title_full_unstemmed Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis
title_short Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis
title_sort epigenetic modulation of gremlin-1/notch pathway in experimental crescentic immune-mediated glomerulonephritis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876310/
https://www.ncbi.nlm.nih.gov/pubmed/35215234
http://dx.doi.org/10.3390/ph15020121
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