High glucose (HG)-induced podocyte injury contributes to the pathogenesis of diabetic nephropathy, a severe complication of diabetes. Bromodomain-containing protein 4 (BRD4) has emerged as a critical regulator for cell injury. However, whether BRD4 participates in HG-induced podocyte injury remains unclear. In this study, we aimed to explore the potential role of BRD4 in regulating HG-induced podocyte injury and its underlying molecular mechanism. HG exposure significantly upregulated BRD4 in podocytes. BRD4 inhibition by small interfering RNA or its chemical inhibitor (JQ1) markedly repressed HG-induced apoptosis and reactive oxygen species (ROS) production. By contrast, BRD4 overexpression exacerbated HG-induced podocyte injury. Moreover, BRD4 inhibition potentiated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling associated with suppression of Kelch-like ECH-associated protein (Keap1). BRD4 inhibition promoted Nrf2 nuclear translocation and upregulated the transcriptional activity of Nrf2/antioxidant response element (ARE). However, Nrf2 silencing partially reversed BRD4-inhibition-mediated protection against HG-induced podocyte injury. Overall, these results suggest that BRD4 inhibition confers cytoprotection against HG injury in podocytes through potentiation of Nrf2/ARE antioxidant signaling. This finding implicates BRD4/Nrf2/ARE signaling in the pathogenesis of diabetic nephropathy.

中文翻译：

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BRD4通过调节Keap1 / Nrf2 / ARE信号转导导致高糖诱导的足细胞损伤。

高葡萄糖（HG）诱导的足细胞损伤导致糖尿病性肾病（糖尿病的一种严重并发症）的发病机理。含溴结构域的蛋白质4（BRD4）已成为细胞损伤的关键调节剂。但是，BRD4是否参与HG诱导的足细胞损伤尚不清楚。在这项研究中，我们旨在探讨BRD4在调节HG诱导的足细胞损伤中的潜在作用及其潜在的分子机制。HG暴露显着上调了足细胞中的BRD4。小干扰RNA或其化学抑制剂（JQ1）对BRD4的抑制作用显着抑制了HG诱导的细胞凋亡和活性氧（ROS）的产生。相比之下，BRD4过表达加剧了HG诱导的足细胞损伤。而且，BRD4抑制增强了与抑制Kelch样ECH相关蛋白（Keap1）相关的核因子（类胡萝卜素2）样2（Nrf2）信号传导。BRD4抑制促进Nrf2核易位并上调Nrf2 /抗氧化反应元件（ARE）的转录活性。但是，Nrf2沉默部分逆转了BRD4抑制介导的针对HG诱导的足细胞损伤的保护作用。总体而言，这些结果表明，通过增强Nrf2 / ARE抗氧化剂信号传导，BRD4抑制作用赋予针对足细胞HG损伤的细胞保护作用。这一发现暗示了BRD4 / Nrf2 / ARE信号传导在糖尿病性肾病的发病机理中。BRD4抑制促进Nrf2核易位并上调Nrf2 /抗氧化反应元件（ARE）的转录活性。但是，Nrf2沉默部分逆转了BRD4抑制介导的针对HG诱导足细胞损伤的保护作用。总体而言，这些结果表明，通过增强Nrf2 / ARE抗氧化剂信号传导，BRD4抑制作用赋予针对足细胞HG损伤的细胞保护作用。这一发现暗示了BRD4 / Nrf2 / ARE信号传导在糖尿病性肾病的发病机理中。BRD4抑制促进Nrf2核易位并上调Nrf2 /抗氧化反应元件（ARE）的转录活性。但是，Nrf2沉默部分逆转了BRD4抑制介导的针对HG诱导的足细胞损伤的保护作用。总体而言，这些结果表明，通过增强Nrf2 / ARE抗氧化剂信号传导，BRD4抑制作用赋予针对足细胞HG损伤的细胞保护作用。这一发现暗示了BRD4 / Nrf2 / ARE信号传导在糖尿病性肾病的发病机理中。