Hou Yali, Li Yaru, Li Jian, Zhao Xiujuan
Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, 194 Xuefu Road, Harbin, 150081, Heilongjiang, China.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr 25. doi: 10.1007/s00210-025-04186-9.
Depression is a serious mental disease, and its accompanying abnormal changes in peripheral organs, including the kidney, are easy to be ignored. The metabolic abnormalities of the kidney and other organs will inevitably affect the progress of depression through the circulatory system. Quercetin has attracted much attention as a flavonoid with anti-inflammatory, antioxidant, neuroprotective, and antidepressant potential. Chronic unpredictable mild stress (CUMS) model is a reliable and effective animal model of depression. We hypothesize that quercetin has the potential to alleviate the abnormalities in renal metabolic profile induced by CUMS. An ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) platform was used to analyze renal metabolites, and the obtained data were analyzed using the Progenesis QI software for peak alignment, peak picking, and data normalization. Based on the data processing method with fold change > 2 or < 0.5, the false discovery rate corrected was p < 0.05, and a variable importance in projection score was > 1; a total of 16 differential metabolites were identified, including L-histidine, D-glucose 1-phosphate, cytidine, D-Ribulose 5-phosphate, D-xylulose 5-phosphate, uridine monophosphate (UMP), uracil, glucuronide, prostaglandin-F2α (PGF2ɑ), arachidonic acid, 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), 14,15-epoxyeicosatrienoic acid (14,15-EET), deoxycytidine, anserine, carnosine, and PC (14:0). Among them, the intensities of anserine, carnosine, L-histidine, and 14,15-EET were significantly reduced (p < 0.01), while the intensities of other metabolites were significantly increased in the CUMS group compared with the control group (p < 0.01). When CUMS model rats received high-dose quercetin treatment, the intensities of above differential metabolites were significantly restored (p < 0.05 or p < 0.01). Further, pathway enrichment analysis revealed abnormalities in arachidonic acid (AA) metabolism, pyrimidine metabolism, amino acid metabolism, and pentose and glucuronide acid interconversion in the kidney. The renal histopathological examination revealed CUMS induced renal tubular epithelial cell shedding and glomerular atrophy. High-dose quercetin can improve renal metabolic disorders and renal pathological changes caused by CUMS. Mechanistically, quercetin improves renal metabolic disorders by enhancing the antioxidant capacity and inhibiting the secretion of inflammatory factors. Moreover, quercetin can regulate renal AA metabolism disorder by inhibiting soluble epoxide hydrolase activity. High-dose quercetin (50 mg/kg bw) has a certain protective effect on kidney damage induced by CUMS, providing new strategies for quercetin to prevent depression.
抑郁症是一种严重的精神疾病，其伴随的包括肾脏在内的外周器官的异常变化很容易被忽视。肾脏和其他器官的代谢异常将不可避免地通过循环系统影响抑郁症的进展。槲皮素作为一种具有抗炎、抗氧化、神经保护和抗抑郁潜力的黄酮类化合物，已引起广泛关注。慢性不可预测轻度应激（CUMS）模型是一种可靠且有效的抑郁症动物模型。我们假设槲皮素具有缓解CUMS诱导的肾脏代谢谱异常的潜力。使用超高效液相色谱-四极杆飞行时间质谱（UPLC-QTOF-MS）平台分析肾脏代谢物，并使用Progenesis QI软件对获得的数据进行峰对齐、峰提取和数据归一化分析。基于变化倍数>2或<0.5的数据处理方法，错误发现率校正后p<0.05且投影变量重要性得分>1；共鉴定出16种差异代谢物，包括L-组氨酸、D-葡萄糖1-磷酸、胞苷、D-核糖-5-磷酸、D-木酮糖-5-磷酸、尿苷单磷酸（UMP）、尿嘧啶、葡糖醛酸、前列腺素-F2α（PGF2ɑ）、花生四烯酸、14,15-二羟基二十碳三烯酸（14,15-DHET）、14,15-环氧二十碳三烯酸（14,15-EET）、脱氧胞苷、鹅肌肽、肌肽和PC（14:0）。其中，CUMS组与对照组相比，鹅肌肽、肌肽、L-组氨酸和14,15-EET的强度显著降低（p<0.01），而其他代谢物的强度显著增加（p<0.01）。当CUMS模型大鼠接受高剂量槲皮素治疗时，上述差异代谢物的强度显著恢复（p<0.05或p<0.01）。此外，通路富集分析显示肾脏中花生四烯酸（AA）代谢、嘧啶代谢、氨基酸代谢以及戊糖和葡糖醛酸相互转化存在异常。肾脏组织病理学检查显示CUMS诱导肾小管上皮细胞脱落和肾小球萎缩。高剂量槲皮素可改善CUMS引起的肾脏代谢紊乱和肾脏病理变化。机制上，槲皮素通过增强抗氧化能力和抑制炎症因子分泌来改善肾脏代谢紊乱。此外，槲皮素可通过抑制可溶性环氧化物水解酶活性来调节肾脏AA代谢紊乱。高剂量槲皮素（50mg/kg体重）对CUMS诱导的肾脏损伤具有一定的保护作用，为槲皮素预防抑郁症提供了新策略。
