Epigenetic regulator BRD4 is involved in cadmium-induced acute kidney injury via contributing to lysosomal dysfunction, autophagy blockade and oxidative stress

Abstract

Cadmium (Cd) is a known nephrotoxic heavy metal and proximal tubules are the major target of Cd-induced acute kidney injury (AKI). We previously demonstrated that lysosomal dysfunction and dysregulated autophagy contribute to Cd-induced AKI. Recent studies have revealed that bromodomain-containing protein 4 (BRD4) is a transcriptional repressor of autophagy and lysosomal function. Hence, in vivo and in vitro studies were performed to clarify the role of BRD4 in Cd-induced AKI. Firstly, Cd has no effect on BRD4 expression levels, but increases H4K16 acetylation. Resultantly, Cd promotes the recruitment of BRD4 to lysosomal gene promoter regions to make it as a transcriptional regulator. Pharmacological and genetic inhibition of BRD4 alleviates Cd-inhibited lysosomal gene transcript levels and lysosomal function, leading to the alleviation of Cd-induced autophagy inhibition. Moreover, inhibition of BRD4 relieves Cd-induced oxidative stress and concurrent cytotoxicity, which is counteracted by the inhibition of autophagy via Atg5 knockdown, indicating that alleviation of oxidative stress by BRD4 inhibition is ascribed to its restoration of autophagic flux. Collectively, these results demonstrate that BRD4 acts as a transcriptional repressor to mediate lysosomal dysfunction, autophagy blockade and oxidative stress during Cd exposure, which may be a potential therapeutic target for Cd-induced AKI.

Keywords: Acute kidney injury; Autophagy; BRD4; Cadmium; Lysosome.