Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt B):113159. doi: 10.1016/j.intimp.2024.113159. Epub 2024 Sep 19.
The role of BMAL1 in various diseases remains unclear, particularly its impact on sepsis-induced acute kidney injury (AKI). This study aims to investigate the role of BMAL1 in sepsis-induced AKI and its potential effects on cell ferroptosis. Initially, we assessed BMAL1 expression levels in mice treated with sepsis-induced AKI (via LPS injection) and in LPS-stimulated renal tubular epithelial cells. Subsequently, we explored the correlation between BMAL1 and ferroptosis using sequencing technology, validating our findings throughout experimental approaches. To further elucidate BMAL1's specific effects on AKI-related ferroptosis, we constructed BMAL1 overexpression models in mice and cells, analysing its impact on AKI and ferroptosis both in vivo and in vitro. Furthermore, using transcriptome sequencing technology, we identified key BMAL1-regulated genes and their associated biological pathways, validating these findings through in vivo and in vitro experiments.
Our findings indicate decreased BMAL1 expression in sepsis-induced AKI. BMAL1 overexpression effectively mitigated renal tubular injury by reducing ferroptosis levels in renal tubular epithelial cells. Using transcriptome sequencing and ChIP-qPCR technology, we identified YAP as a target of BMAL1. The overexpression of BMAL1 significantly reduced the transcriptional activity of YAP and inhibited the Hippo signalling pathway. Treatment with the Hippo inhibitor Verteporfin (VP) reversed the BMAL1-downregulation-induced damage. Additionally, our study revealed that YAP positively regulates ACSL4 gene expression and its downstream signalling pathways.
This study demonstrates that BMAL1 overexpression alleviates renal tubular epithelial cell injury and ferroptosis by inhibiting YAP expression and the Hippo pathway, thereby exerting protective effects in sepsis-induced AKI. These findings underscore the therapeutic potential of targeting BMAL1 in managing sepsis-induced AKI.
BMAL1 在各种疾病中的作用尚不清楚，特别是其对脓毒症诱导的急性肾损伤（AKI）的影响。本研究旨在探讨 BMAL1 在脓毒症诱导的 AKI 中的作用及其对细胞铁死亡的潜在影响。首先，我们评估了脓毒症诱导 AKI（通过 LPS 注射）小鼠和 LPS 刺激的肾小管上皮细胞中 BMAL1 的表达水平。随后，我们使用测序技术探讨了 BMAL1 与铁死亡之间的相关性，通过实验方法验证了我们的发现。为了进一步阐明 BMAL1 对 AKI 相关铁死亡的具体作用，我们在小鼠和细胞中构建了 BMAL1 过表达模型，分析了其对 AKI 和铁死亡的影响，包括体内和体外实验。此外，我们还使用转录组测序技术鉴定了关键的 BMAL1 调控基因及其相关的生物学途径，并通过体内和体外实验验证了这些发现。
我们的研究结果表明，在脓毒症诱导的 AKI 中，BMAL1 的表达降低。BMAL1 过表达通过降低肾小管上皮细胞中铁死亡水平，有效减轻肾小管损伤。通过转录组测序和 ChIP-qPCR 技术，我们发现 YAP 是 BMAL1 的靶基因。BMAL1 的过表达显著降低了 YAP 的转录活性并抑制了 Hippo 信号通路。用 Hippo 抑制剂 Verteporfin（VP）处理可逆转 BMAL1 下调诱导的损伤。此外，我们的研究还表明，YAP 正向调节 ACSL4 基因的表达及其下游信号通路。
本研究表明，BMAL1 过表达通过抑制 YAP 表达和 Hippo 通路，减轻肾小管上皮细胞损伤和铁死亡，从而在脓毒症诱导的 AKI 中发挥保护作用。这些发现强调了靶向 BMAL1 治疗脓毒症诱导的 AKI 的治疗潜力。
