Antioxidants · 14 authors, 7 centres
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This study demonstrates that the BET protein inhibitor JQ1 reduces peritoneal membrane thickening, inflammatory cell infiltration, and fibrosis in a chlorhexidine gluconate-induced mouse model of peritoneal damage. JQ1 also inhibits proinflammatory and profibrotic gene expression in cultured mesothelial cells from peritoneal dialysis patients. These findings suggest BET inhibitors as a potential therapeutic option to prevent peritoneal damage in patients undergoing peritoneal dialysis.
**Background:** Peritoneal dialysis (PD) is a common replacement therapy for end-stage kidney disease (ESKD), but long-term exposure to PD fluids can cause peritoneal membrane (PM) damage through inflammation, mesothelial-to-mesenchymal transition (MMT), and fibrosis, leading to ultrafiltration failure. Epigenetic drugs targeting bromodomain and extra-terminal domain (BET) proteins have shown anti-inflammatory and antifibrotic effects in various diseases, but their role in peritoneal damage was unknown. This study evaluated the BET inhibitor JQ1 in a mouse model of chlorhexidine gluconate (CHX)-induced peritoneal damage and in cultured mesothelial cells.
**Methods:** Peritoneal damage was induced in adult male C57BL/6 mice by daily intraperitoneal injections of 0.1% CHX (10 mL/kg) for 10 consecutive days. A group of CHX-treated mice (n=8) also received JQ1 (50 mg/kg/day) intraperitoneally, while CHX-only mice (n=6) and untreated controls (n=4) were included. Peritoneal tissue was analyzed by histology (Masson's trichrome), immunohistochemistry (CD3, F4/80, p-NRF2), western blot (p-NF-κB p65, p-IκBα, fibronectin, p-SMAD2/3), and qPCR for inflammatory, fibrotic, and oxidative stress genes. In vitro, the human mesothelial cell line MeT-5A and effluent-derived primary mesothelial cells from PD patients were pretreated with 1 μM JQ1 for 3 h, then stimulated with TNF-α (5 ng/mL) for inflammation or TGF-β1 (2 ng/mL) + IL-1β (5 ng/mL) for MMT/fibrosis for 24 h. Gene expression and protein levels were measured by qPCR and western blot.
**Key Results:** In vivo, CHX induced PM thickening (submesothelial zone collagen deposition) and inflammatory cell infiltration (CD3+ T cells and F4/80+ macrophages), which were significantly reduced by JQ1. JQ1 decreased CHX-induced gene expression of MMT markers (Snai1, Cdh2, Acta2) and tended to reduce fibronectin and p-SMAD2/3 protein levels. JQ1 significantly reduced p-IκBα levels (indicating NF-κB pathway inhibition) and downregulated proinflammatory chemokine (Ccl5, Ccl2, Ccl8, Cxcl10) and cytokine (Il1b, Tnfa) gene expression. JQ1 also restored CHX-induced changes in oxidative stress markers: it normalized Nox1 and Nox4 gene expression, restored Ppargc1a (PGC-1α) levels, and reduced the number of p-NRF2-positive cells in the peritoneum. In vitro, JQ1 (1 μM) significantly downregulated TGF-β1+IL-1β-induced MMT markers (SNAI1, CDH2, CCN2, VIM, FN1, COL1A1, ACTA2) and fibronectin protein in MeT-5A cells. In both MeT-5A and primary mesothelial cells, JQ1 strongly suppressed TNF-α-induced proinflammatory genes (CCL2, CCL5, CXCL10, IL1B, IL-6). JQ1 also modulated oxidative stress genes, decreasing NOX1, NOX4, NFE2L2, and CAT expression, while HMOX1 and SOD1 were upregulated or unchanged.
**Clinical Implications:** This study provides the first preclinical evidence that BET inhibition with JQ1 ameliorates peritoneal damage by targeting inflammation, fibrosis, and oxidative stress pathways, including NF-κB and NRF2. These findings suggest that BET inhibitors could be a novel therapeutic strategy to preserve peritoneal membrane function in PD patients, potentially preventing ultrafiltration failure and prolonging PD therapy. The results support further investigation in clinical trials, especially given that BET inhibitors like apabetalone are already being tested in other ESKD-related conditions.