Diclofenac (DF)-induced acute kidney injury (AKI) is characterized by glomerular dysfunction and acute tubular necrosis. Due to limited treatment approaches, effective and safe drug therapy to protect against such AKI is still needed. Diacetylrhein (DAR), an anthraquinone derivative, has different antioxidant and anti-inflammatory properties. Therefore, the aim of the current study was to investigate the renoprotective effect of DAR on DF-induced AKI while elucidating the potential underlying mechanism. Our results showed that DAR (50 and 100 mg/kg) markedly abrogated DF-induced kidney dysfunction decreasing SCr, BUN, serum NGAL, and serum KIM1 levels. Moreover, DAR treatment remarkably maintained renal redox balance and reduced the levels of pro-inflammatory biomarkers in the kidney. Mechanistically, DAR boosted Nrf2/HO-1 antioxidant and anti-inflammatory response in the kidney while suppressing renal TLR4/NF-κB and NLRP3/caspase-1 inflammatory signaling pathways. In addition, DAR markedly inhibited renal pyroptosis via targeting of GSDMD activation. Collectively, this study confirmed that the interplay between Nrf2/HO-1 and TLR4/NF-κB/NLRP3/Caspase-1 signaling pathways and pyroptotic cell death mediates DF-induced AKI and reported that DAR has a dose-dependent renoprotective effect on DF-induced AKI in rats. This effect is due to powerful antioxidant, anti-inflammatory, and anti-pyroptotic activities that could provide a promising treatment approach to protect against DF-induced AKI.

中文翻译：

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二乙酰大黄酸通过调节 Nrf2/NF-κB/NLRP3/GSDMD 信号通路对双氯芬酸诱导的大鼠急性肾损伤的肾脏保护作用

双氯芬酸（DF）引起的急性肾损伤（AKI）的特点是肾小球功能障碍和急性肾小管坏死。由于治疗方法有限，仍然需要有效且安全的药物治疗来预防此类 AKI。二乙酰大黄酸 (DAR) 是一种蒽醌衍生物，具有不同的抗氧化和抗炎特性。因此，本研究的目的是研究 DAR 对 DF 诱导的 AKI 的肾脏保护作用，同时阐明潜在的潜在机制。我们的结果表明，DAR（50 和 100 mg/kg）显着消除 DF 诱导的肾功能障碍，降低 SCr、BUN、血清 NGAL 和血清 KIM1 水平。此外，DAR 治疗显着维持了肾脏氧化还原平衡并降低了肾脏中促炎生物标志物的水平。从机制上讲，DAR 增强肾脏中的 Nrf2/HO-1 抗氧化和抗炎反应，同时抑制肾脏 TLR4/NF-κB 和 NLRP3/caspase-1 炎症信号通路。此外，DAR 通过靶向 GSDMD 激活显着抑制肾焦亡。总的来说，这项研究证实了 Nrf2/HO-1 和 TLR4/NF-κB/NLRP3/Caspase-1 信号通路之间的相互作用以及焦亡细胞死亡介导 DF 诱导的 AKI，并报道 DAR 对 DF 具有剂量依赖性肾脏保护作用- 诱导大鼠 AKI。这种作用归因于强大的抗氧化、抗炎和抗焦亡活性，这些活性可以提供一种有前途的治疗方法来预防 DF 诱导的 AKI。