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Title: | Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis |
Author: | Tejedor Santamaria, Lucia Morgado Pascual, Jose Luis Marquez Expósito, Laura Suarez Alvarez, Beatriz Rodrigues Diez, Raul R. Tejera Muñoz, Antonio Marchant, Vanessa Mezzano, Sergio López Larrea, Carlos Sola, Anna Fernandez Juarez, Gema Maria Ortiz, Alberto Rayego Mateos, Sandra Ruiz Ortega, Marta |
Keywords: | Malalties del ronyó Epigenètica Kidney diseases Epigenetics |
Issue Date: | 20-Jan-2022 |
Publisher: | MDPI AG |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.3390/ph15020121 |
It is part of: | Pharmaceuticals, 2022, vol. 15, num. 2 |
URI: | http://hdl.handle.net/2445/185139 |
Related resource: | https://doi.org/10.3390/ph15020121 |
ISSN: | 1424-8247 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) Publicacions de projectes de recerca finançats per la UE |
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pharmaceuticals-15-00121-v2.pdf | 2.66 MB | Adobe PDF | View/Open |
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