Abstract：
Many inflammatory disorders, including diabetic kidney disease (DKD), are associated with pyroptosis, a type of inflammation-regulated cell death. The purpose of this work was to ascertain the effects of apabetalone, which targets BRD4, a specific inhibitor of the bromodomain (BRD) and extra-terminal (BET) proteins that target bromodomain 2, on kidney injury in DKD. This study utilized pharmacological and genetic approaches to investigate the effects of apabetalone on pyroptosis in db/db mice and human tubular epithelial cells (HK-2). BRD4 levels were elevated in HK-2 cells exposed to high glucose and in db/db mice. Modulating BRD4 levels led to changes in the generation of inflammatory cytokines and cell pyroptosis linked to NLRP3 inflammasome in HK-2 cells and db/db mice. Likewise, these cellular processes were mitigated by apabetalone through inhibition BRD4. Apabetalone or BRD4 siRNA suppressed PLK1 expression in HK-2 cells under high glucose by P300-dependent H3K27 acetylation on the PLK1 gene promoter, as demonstrated through chromatin immunoprecipitation and immunoprecipitation assays. To summarize, apabetalone relieves renal proptosis and fibrosis in DKD. BRD4 regulates the P300/H3K27ac/PLK1 axis, leading to the activation of the NLRP3 inflammasome and subsequent cell pyroptosis, inflammation, and fibrosis. These results may provide new perspectives on DKD treatment.
摘要：
许多炎症性疾病，包括糖尿病肾病（DKD），与焦亡有关，一种炎症调节的细胞死亡。这项工作的目的是确定阿帕贝酮的效果，它靶向BRD4，溴结构域（BRD）和靶向溴结构域2的末端外（BET）蛋白的特异性抑制剂，对DKD的肾损伤。这项研究利用药理学和遗传学方法来研究阿帕贝酮对db/db小鼠和人肾小管上皮细胞（HK-2）的焦亡的影响。BRD4水平在暴露于高葡萄糖的HK-2细胞中和在db/db小鼠中升高。调节BRD4水平导致HK-2细胞和db/db小鼠中与NLRP3炎性体相关的炎性细胞因子的产生和细胞焦亡的变化。同样，阿帕贝酮通过抑制BRD4缓解了这些细胞过程.阿帕贝酮或BRD4siRNA通过PLK1基因启动子上的P300依赖性H3K27乙酰化抑制高糖下HK-2细胞中PLK1的表达，通过染色质免疫沉淀和免疫沉淀试验证明。总结一下,阿帕贝酮可缓解DKD的肾脏突出和纤维化。BRD4调节P300/H3K27ac/PLK1轴，导致NLRP3炎性体的激活和随后的细胞焦亡，炎症,和纤维化。这些结果可能为DKD治疗提供新的视角。
