Abstract
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.
Funder
Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union
Red de Investigación Renal REDINREN
European Union—NextGenerationEU, Sociedad Española de Nefrología
“NOVELREN-CM: Enfermedad renal crónica: nuevas Estrategias para la prevención, Diagnóstico y tratamiento”
Juan de la Cierva formación grant
Juan de la Cierva incorporación grant
Innovation programme under the Marie Skłodowska-Curie grant of the European Union’s Horizon 2020
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Cited by
4 articles.
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