Zhang Jialing, Dong Xingtong, Pang Qi, Zhang Aihua
Department of Nephrology, Xuanwu Hospital, Capital Medical University, Beijing, China.
National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.
Mediators Inflamm. 2024 Dec 11;2024:2662362. doi: 10.1155/mi/2662362. eCollection 2024.
Cognitive impairment is a vital complication of chronic kidney disease (CKD). The effect of irisin on CKD-induced cognitive impairment remains unclear. In the present study, we aimed to investigate the role of Irisin in mitigating cognitive impairment and explore the underlying mechanisms in CKD. A CKD mice model was established by adenine. Cognitive function was assessed via the novel object recognition (NOR). Interleukin-1 (IL-1) levels were measured by enzyme-linked immunosorbent assay (ELISA), while pyroptosis-related protein expression was analyzed using western blotting. Our data showed an upregulation of cell pyroptosis in hippocampus tissues of CKD mice, accompanied by significant cognitive impairment. Pyroptosis and cognitive impairment was both improved by Irisin treatment in vivo. Additionally, irisin markedly downregulated pyroptosis levels through aryl hydrocarbon receptor (AhR)/NF-B p65 signaling in HT-22 cells pretreated with indoxyl sulfate (IS). In vitro experiments further confirmed that pyroptosis was inhibited by AhR and NF-B p65 inhibitors. We first demonstrated that irisin alleviated cognitive impairment by inhibiting AhR/NF-B-NLRP3-mediated pyroptosis of hippocampal neurons in CKD. Overall, irisin may have the potential to serve as a critical antipyroptotic agent for improving CKD-induced cognitive impairment.
认知障碍是慢性肾脏病（CKD）的一种重要并发症。鸢尾素对CKD所致认知障碍的影响尚不清楚。在本研究中，我们旨在探讨鸢尾素在减轻认知障碍中的作用，并探索CKD的潜在机制。通过腺嘌呤建立CKD小鼠模型。通过新物体识别（NOR）评估认知功能。采用酶联免疫吸附测定（ELISA）检测白细胞介素-1（IL-1）水平，同时用蛋白质免疫印迹法分析焦亡相关蛋白表达。我们的数据显示，CKD小鼠海马组织中细胞焦亡上调，同时伴有明显的认知障碍。鸢尾素治疗在体内改善了焦亡和认知障碍。此外，在经硫酸吲哚酚（IS）预处理的HT-22细胞中，鸢尾素通过芳烃受体（AhR）/核因子-κB p65信号通路显著下调焦亡水平。体外实验进一步证实，AhR和核因子-κB p65抑制剂可抑制焦亡。我们首次证明，鸢尾素通过抑制CKD中海马神经元的AhR/核因子-κB-NLRP3介导的焦亡来减轻认知障碍。总体而言，鸢尾素可能有潜力作为一种关键的抗焦亡药物来改善CKD所致的认知障碍。
