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

作者：José Luis Morgado‐Pascual, Beatriz Suárez-Álvarez, Vanessa Marchant, Pamela Estefanía Basantes, Pierre‐Louis Tharaux, Alberto Ortíz, Carlos López‐Larrea, Marta Ruiz‐Ortega, Sandra Rayego‐Mateos · 发表于：International Journal of Molecular Sciences · 年份：2022 · DOI：10.3390/ijms24010486 · 被引用次数：18 · 研究领域：Protein Degradation and Inhibitors、Multiple Myeloma Research and Treatments、Renal Diseases and Glomerulopathies

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 ...