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.
Highlights
Chronic kidney disease (CKD) is defined as abnormalities in kidney structure or function, present for >3 months and with implications for health [1]
We have recently described that Gremlin-1 is a potential urinary biomarker of human anti-neutrophil cytoplasmic antibodies (ANCA)-associated crescentic glomerulonephritis (cGN) [16]
The model of of administration in in mice is commonly used to study mechanisms of of administration mice is commonly used to study mechanisms human cGN. This model is characterized by the proliferation of intrinsic glomerular cells human cGN
Summary
Chronic kidney disease (CKD) is defined as abnormalities in kidney structure or function, present for >3 months and with implications for health [1]. Glomerular kidney disease cause 18% of CKD cases requiring kidney replacement therapy, illustrating the failure of current therapeutic approaches to prevent CKD progression to end-stage renal disease (ESRD) [4]. Is one of the most aggressive forms of CKD, characterized by the proliferation of intrinsic glomerular cells in the Bowman’s space, leading to the formation of crescents that evolve to fibrotic structures and loss of functioning glomeruli [5,6]. The underlying structural kidney damage for the clinical presentation, termed RPGN, is crescentic glomerulonephritis (cGN). Most patients are treated with immunosuppressive therapy, but the residual risk of ESRD remains high despite treatment [2]
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