Division of Nephrology, National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China.
J Cell Mol Med. 2021 Jan;25(2):1035-1047. doi: 10.1111/jcmm.16168. Epub 2020 Dec 6.
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.
急性肾损伤（AKI）是一种由多种病因引起的多因素疾病。芳香烃受体（AhR）是一种配体激活的转录因子，它可以响应配体来诱导或抑制基因表达，从而调节多种生物或病理生理效应。然而，AhR 对 AKI 的影响尚不清楚。在 C57BL/6J 小鼠中，通过单次腹腔注射 50%甘油来诱导横纹肌溶解。夹闭双侧肾蒂 30 分钟，然后去除以刺激肾 I/R 损伤。6-甲酰基吲哚并[3,2-b]咔唑（FICZ）是色氨酸的光氧化产物，与 AhR 具有高亲和力，被用于该研究。体外研究在 HK-2 细胞上进行。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 的处理显著减轻了 AKI 中血清肌酐和尿素的升高。FICZ 减轻了 AKI 模型诱导的肾损伤。AhR 主要在近端肾小管细胞中表达，并可被 FICZ 激活。同时，AKI 在受损肾脏中触发促炎细胞因子的产生，而 FICZ 抑制其表达。此外，FICZ 有效地逆转了 AKI 模型中的细胞凋亡。机制上，AKI 刺激肾脏中 NF-κB 和 JNK 途径的激活，而 FICZ 显著抑制这些相应的蛋白表达。对于体外研究，FICZ 还抑制肌红蛋白或 H/R 刺激的 HK-2 细胞中的炎症和凋亡。总之，FICZ 通过抑制 NF-κB 和 JNK 途径在近端肾小管细胞中抑制炎症和凋亡，从而缓解肌红蛋白溶解和 I/R 诱导的 AKI。
