Acute kidney injury (AKI) is a multifactorial disease of various aetiologies. Aryl hydrocarbon receptor (AhR) is a ligand‐activated transcription factor that responds to ligands to induce or repress gene expressions, thereby regulating a diverse spectrum of biological or pathophysiologic effects. However, the effect of AhR on AKI remains unknown. A single intraperitoneal injection of 50% glycerol was performed to induce rhabdomyolysis in C57BL/6J mice. The bilateral renal pedicles were occluded for 30 minutes and then removed to stimulate renal I/R injury. 6‐formylindolo[3,2‐b]carbazole (FICZ), a photo‐oxidation product of tryptophan with a high affinity for AhR, was used. The in vitro study was performed on HK‐2 cells. Ferrous myoglobin and FICZ was dissolved in the medium in different cell groups. Treatment with AhR agonist FICZ significantly alleviated the elevation of serum creatinine and urea in AKI. AKI modelling‐induced renal damage was attenuated by FICZ. AhR mainly expressed in proximal tubular cells and could be activated by FICZ administration. Meanwhile, AKI triggered the production of pro‐inflammatory cytokines in injured kidneys, while FICZ inhibited their expressions. Furthermore, FICZ effectively reversed cell apoptosis in AKI models. Mechanistically, AKI stimulated the activation of NF‐κB and JNK pathways in the kidneys, while FICZ significantly suppressed these corresponding protein expressions. For the in vitro study, FICZ also inhibited inflammation and apoptosis in myoglobin or H/R‐stimulated HK‐2 cells. In summary, agonism of AhR by FICZ alleviated rhabdomyolysis and I/R‐induced AKI. FICZ inhibited inflammation and apoptosis via suppressing NF‐κB and JNK pathways in proximal tubular cells.

中文翻译：

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6-甲酰基吲哚并[3,2-b]咔唑激活芳基烃受体通过抑制炎症和细胞凋亡减轻急性肾损伤

急性肾损伤（AKI）是一种多种病因的多因素疾病。芳基烃受体 (AhR) 是一种配体激活的转录因子，可响应配体诱导或抑制基因表达，从而调节多种生物学或病理生理学效应。然而，AhR 对 AKI 的影响仍不清楚。单次腹腔注射 50% 甘油诱导 C57BL/6J 小鼠横纹肌溶解。双侧肾蒂闭塞30分钟，然后去除以刺激肾I/R损伤。使用 6-甲酰基吲哚并[3,2-b]咔唑 (FICZ)，一种对 AhR 具有高亲和力的色氨酸光氧化产物。体外研究是在 HK-2 细胞上进行的。亚铁肌红蛋白和FICZ溶解在不同细胞组的培养基中。AhR 激动剂 FICZ 治疗显着缓解了 AKI 中血清肌酐和尿素的升高。FICZ 减轻了 AKI 模型引起的肾损伤。AhR 主要表达于近端肾小管细胞，可通过 FICZ 激活。同时，AKI 触发受损肾脏中促炎细胞因子的产生，而 FICZ 则抑制其表达。此外，FICZ 有效逆转 AKI 模型中的细胞凋亡。从机制上讲，AKI 刺激肾脏中 NF-κB 和 JNK 通路的激活，而 FICZ 显着抑制这些相应的蛋白表达。在体外研究中，FICZ 还抑制肌红蛋白或 H/R 刺激的 HK-2 细胞的炎症和细胞凋亡。总之，FICZ 对 AhR 的激动作用减轻了横纹肌溶解和 I/R 诱导的 AKI。FICZ 通过抑制近端肾小管细胞中的 NF-κB 和 JNK 通路来抑制炎症和细胞凋亡。