Marchant Vanessa, Trionfetti Flavia, Tejedor-Santamaria Lucia, Rayego-Mateos Sandra, Rotili Dante, Bontempi Giulio, Domenici Alessandro, Menè Paolo, Mai Antonello, Martín-Cleary Catalina, Ortiz Alberto, Ramos Adrian M, Strippoli Raffaele, Ruiz-Ortega Marta
Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid, 28040 Madrid, Spain.
RICORS2040, 28029 Madrid, Spain.
Antioxidants (Basel). 2023 Nov 29;12(12):2055. doi: 10.3390/antiox12122055.
Peritoneal dialysis (PD) is a current replacement therapy for end-stage kidney diseases (ESKDs). However, long-term exposure to PD fluids may lead to damage of the peritoneal membrane (PM) through mechanisms involving the activation of the inflammatory response and mesothelial-to-mesenchymal transition (MMT), leading to filtration failure. Peritoneal damage depends on a complex interaction among external stimuli, intrinsic properties of the PM, and subsequent activities of the local innate-adaptive immune system. Epigenetic drugs targeting bromodomain and extra-terminal domain (BET) proteins have shown beneficial effects on different experimental preclinical diseases, mainly by inhibiting proliferative and inflammatory responses. However the effect of BET inhibition on peritoneal damage has not been studied. To this aim, we have evaluated the effects of treatment with the BET inhibitor JQ1 in a mouse model of peritoneal damage induced by chlorhexidine gluconate (CHX). We found that JQ1 ameliorated the CHX-induced PM thickness and inflammatory cell infiltration. Moreover, JQ1 decreased gene overexpression of proinflammatory and profibrotic markers, together with an inhibition of the nuclear factor-κB (NF-κB) pathway. Additionally, JQ1 blocked the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and restored changes in the mRNA expression levels of NADPH oxidases (NOX1 and NOX4) and NRF2/target antioxidant response genes. To corroborate the in vivo findings, we evaluated the effects of the BET inhibitor JQ1 on PD patients' effluent-derived primary mesothelial cells and on the MeT-5A cell line. JQ1 inhibited tumor necrosis factor-α (TNF-α)-induced proinflammatory gene upregulation and restored MMT phenotype changes, together with the downmodulation of oxidative stress. Taken together, these results suggest that BET inhibitors may be a potential therapeutic option to ameliorate peritoneal damage.
腹膜透析（PD）是目前终末期肾病（ESKD）的替代治疗方法。然而，长期接触腹膜透析液可能通过涉及炎症反应激活和间皮-间充质转化（MMT）的机制导致腹膜（PM）损伤，进而导致滤过功能衰竭。腹膜损伤取决于外部刺激、腹膜的内在特性以及局部先天性-适应性免疫系统的后续活动之间的复杂相互作用。靶向溴结构域和额外末端结构域（BET）蛋白的表观遗传药物已显示出对不同实验性临床前疾病具有有益作用，主要是通过抑制增殖和炎症反应。然而，BET抑制对腹膜损伤的影响尚未得到研究。为此，我们评估了BET抑制剂JQ1在葡萄糖酸氯己定（CHX）诱导的腹膜损伤小鼠模型中的治疗效果。我们发现JQ1改善了CHX诱导的腹膜厚度和炎性细胞浸润。此外，JQ1降低了促炎和促纤维化标志物的基因过度表达，同时抑制了核因子-κB（NF-κB）途径。此外，JQ1阻断了核因子红细胞2相关因子2（NRF2）的激活，并恢复了烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX1和NOX4）以及NRF2/靶抗氧化反应基因的mRNA表达水平变化。为了证实体内研究结果，我们评估了BET抑制剂JQ1对腹膜透析患者流出液来源的原代间皮细胞和MeT-5A细胞系的影响。JQ1抑制肿瘤坏死因子-α（TNF-α）诱导的促炎基因上调，并恢复MMT表型变化，同时下调氧化应激。综上所述，这些结果表明BET抑制剂可能是改善腹膜损伤的潜在治疗选择。
