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Biochimie. 2019 Jul 17;165:100-107. doi: 10.1016/j.biochi.2019.07.012. [Epub ahead of print]

BRD4 contributes to high-glucose-induced podocyte injury by modulating Keap1/Nrf2/ARE signaling.

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Department of Endocrinology, the Ninth Hospital of Xian, Xi'an, 710054, Shaanxi Province, China. Electronic address:
Department of Endocrinology, the Ninth Hospital of Xian, Xi'an, 710054, Shaanxi Province, China.


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.


BRD4; Diabetic nephropathy; High glucose; Nrf2; Podocyte

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