Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, 1 Semmelweis utca, Szeged, H-6725, Hungary.
Department of Biochemistry, Bach Mai Hospital, 78 Giai Phong Street, Phuong Mai, Dong Da, Hanoi, 100000, Vietnam.
Pflugers Arch. 2024 Feb;476(2):179-196. doi: 10.1007/s00424-023-02884-y. Epub 2023 Nov 22.
Chronic kidney disease (CKD) is associated with anxiety; however, its exact mechanism is not well understood. Therefore, the aim of the present study was to assess the effect of moderate CKD on anxiety in rats. 5/6 nephrectomy was performed in male Wistar rats. 7 weeks after, anxiety-like behavior was assessed by elevated plus maze (EPM), open field (OF), and marble burying (MB) tests. At weeks 8 and 9, urinalysis was performed, and blood and amygdala samples were collected, respectively. In the amygdala, the gene expression of Avp and the gene and protein expression of Crh, Crhr1, and Crhr2 were analyzed. Furthermore, the plasma concentration of corticosterone, uremic toxins, and tryptophan metabolites was measured by UHPLC-MS/MS. Laboratory tests confirmed the development of CKD. In the CKD group, the closed arm time increased; the central time and the total number of entries decreased in the EPM. There was a reduction in rearing, central distance and time in the OF, and fewer interactions with marbles were detected during MB. CKD evoked an upregulation of gene expression of Crh, Crhr1, and Crhr2, but not Avp, in the amygdala. However, there was no alteration in protein expression. In the CKD group, plasma concentrations of p-cresyl-sulfate, indoxyl-sulfate, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid, xanthurenic acid, 5-hydroxyindoleacetic acid, picolinic acid, and quinolinic acid increased. However, the levels of tryptophan, tryptamine, 5-hydroxytryptophan, serotonin, and tyrosine decreased. In conclusion, moderate CKD evoked anxiety-like behavior that might be mediated by the accumulation of uremic toxins and metabolites of the kynurenine pathway, but the contribution of the amygdalar CRH system to the development of anxiety seems to be negligible at this stage.
慢性肾脏病（CKD）与焦虑有关；然而，其确切机制尚不清楚。因此，本研究旨在评估中度 CKD 对大鼠焦虑的影响。雄性 Wistar 大鼠行 5/6 肾切除术。7 周后，通过高架十字迷宫（EPM）、旷场（OF）和埋珠试验评估焦虑样行为。第 8 周和第 9 周，进行尿分析，并分别采集血液和杏仁核样本。在杏仁核中，分析了 Avp 的基因表达以及 Crh、Crhr1 和 Crhr2 的基因和蛋白表达。此外，通过 UHPLC-MS/MS 测定了皮质酮、尿毒症毒素和色氨酸代谢物的血浆浓度。实验室检测证实了 CKD 的发展。在 CKD 组中，EPM 的闭臂时间增加；中央时间和总进入次数减少。OF 中的翻身、中央距离和时间减少，在埋珠试验中与大理石的互动减少。CKD 导致杏仁核中 Crh、Crhr1 和 Crhr2 的基因表达上调，但 Avp 没有改变。然而，蛋白表达没有改变。在 CKD 组中，p- 对甲酚硫酸盐、吲哚硫酸盐、犬尿氨酸、犬尿喹啉酸、3-羟基犬尿氨酸、邻氨基苯甲酸、黄尿酸、5- 羟吲哚乙酸、吡啶酸和喹啉酸的血浆浓度增加。然而，色氨酸、色胺、5- 羟色氨酸、血清素和酪氨酸的水平降低。总之，中度 CKD 引起的焦虑样行为可能是由尿毒症毒素和犬尿氨酸途径代谢物的积累介导的，但在这个阶段，杏仁核 CRH 系统对焦虑的发展的贡献似乎可以忽略不计。
