背景:尿素,蛋白质代谢的最终产物,长期以来一直被认为具有微不足道的毒性。我们先前的研究显示尿素转运蛋白(UT)B基因敲除小鼠的抑郁表型,这表明尿素代谢异常可能导致抑郁症。这项研究的目的是使用临床数据和动物模型确定大脑中尿素的积累是否是导致抑郁症的关键因素。
方法:采用荟萃分析的方法来确定抑郁症与慢性疾病之间的关系。比较患者和健康对照组的脑功能磁共振成像(fMRI)扫描和常见生化指标。我们用行为测试,电生理学,和分子谱分析技术来研究小鼠模型中的功能作用和分子基础。
结果:进行荟萃分析后,我们针对慢性肾脏病(CKD)和抑郁症之间的相关性.在CKD小鼠模型和患者队列中,抑郁是由内侧前额叶皮层受损引起的。扩大的队列表明尿素是抑郁症的原因。在老鼠身上,尿素足以诱发抑郁,中断长时程增强(LTP)并在几个模型中导致突触丢失。mTORC1-S6K途径抑制是尿素作用所必需的。最后,我们发现尿素的水解产物,氰酸盐,也参与了这种病理生理学。
结论:这些数据表明,脑内尿素蓄积是引起抑郁的独立因素,绕过心理社会压力。尿素或氰酸酯氨基甲酸酯化mTOR以抑制mTORC1-S6K依赖性树突状蛋白合成,诱导mPFC突触可塑性受损和抑郁样行为。CKD患者只有通过严格的血尿素管理才能减轻抑郁症。
BACKGROUND: Urea, the end product of protein metabolism, has been considered to have negligible toxicity for a long time. Our previous study showed a depression phenotype in urea transporter (UT) B knockout mice, which suggests that abnormal urea metabolism may cause depression. The purpose of this study was to determine if urea accumulation in brain is a key factor causing depression using clinical data and animal models.
METHODS: A meta-analysis was used to identify the relationship between depression and chronic diseases. Functional Magnetic Resonance Imaging (fMRI) brain scans and common biochemical indexes were compared between the patients and healthy controls. We used behavioural tests, electrophysiology, and molecular profiling techniques to investigate the functional role and molecular basis in mouse models.
RESULTS: After performing a meta-analysis, we targeted the relevance between chronic kidney disease (CKD) and depression. In a CKD mouse model and a patient cohort, depression was induced by impairing the medial prefrontal cortex. The enlarged cohort suggested that urea was responsible for depression. In mice, urea was sufficient to induce depression, interrupt long-term potentiation (LTP) and cause loss of synapses in several models. The mTORC1-S6K pathway inhibition was necessary for the effect of urea. Lastly, we identified that the hydrolysate of urea, cyanate, was also involved in this pathophysiology.
CONCLUSIONS: These data indicate that urea accumulation in brain is an independent factor causing depression, bypassing the psychosocial stress. Urea or cyanate carbamylates mTOR to inhibit the mTORC1-S6K dependent dendritic protein synthesis, inducing impairment of synaptic plasticity in mPFC and depression-like behaviour. CKD patients may be able to attenuate depression only by strict management of blood urea.