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Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis
Lucia Tejedor-Santamaria1,2, Jose Luis Morgado-Pascual1,2, Laura Marquez-Exposito1,2
1Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain.
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.
Insights
Bromodomain and extraterminal domain (BET) inhibitors, a novel epigenetic drug class, show promise in treating crescentic glomerulonephritis by regulating Gremlin-1 and the NOTCH pathway, offering potential new therapies for this severe kidney disease.
Area of Science:
- Nephrology
- Immunology
- Epigenetics
Background:
- Crescentic glomerulonephritis is a severe autoimmune kidney disease with limited treatment options and high rates of end-stage renal disease.
- Current immunosuppressive therapies have modest efficacy and significant side effects.
- Epigenetic drugs, specifically bromodomain and extraterminal domain (BET) inhibitors (iBETs), represent a potential new therapeutic avenue.
Purpose of the Study:
- To investigate the therapeutic potential of iBETs in experimental crescentic glomerulonephritis.
- To determine if iBETs can modulate Gremlin-1 expression, a marker of disease progression.
- To explore the role of the NOTCH pathway in the protective effects of iBETs.
Main Methods:
- Utilized a mouse model of anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS).
- Administered the iBET JQ1 to NTS-injected mice.
- Performed chromatin immunoprecipitation assays to assess BRD4 binding to the Gremlin-1 promoter.
- Analyzed gene expression of Gremlin-1, Hes-1, and Hey-1.
Main Results:
- JQ1 treatment inhibited renal Gremlin-1 overexpression in NTS-injected mice.
- iBET JQ1 diminished glomerular damage and restored podocyte numbers.
- BRD4 was found to bind the Gremlin-1 gene promoter in injured kidneys, indicating epigenetic regulation.
- JQ1 blocked BRD4 binding, inhibited Gremlin-1 transcription, and modulated NOTCH pathway gene expression (Hes-1, Hey-1).
Conclusions:
- iBETs, like JQ1, can epigenetically regulate Gremlin-1 expression in experimental crescentic glomerulonephritis.
- The beneficial effects of iBETs involve modulation of the NOTCH pathway.
- Epigenetic therapies targeting BET proteins offer a promising strategy for treating rapidly progressive crescentic glomerulonephritis.
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