Untargeted metabolomics revealed that quercetin improves rat renal metabolic disorders induced by chronic unpredictable mild stress.

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.