High urea induces depression and LTP impairment through mTOR signalling suppression caused by carbamylation

• Type of Material: Article
• Authors: Hongkai Wang, Peking University; Boyue Huang, Peking University; Weiling Wang, Peking University; Jinfang Li, Chongqing Medical University; Yi Chen, Chongqing Medical University; Trevor Flynn, University of California San Francisco; Meng Zhao, Chongqing Medical University; Zhiming Zhou, Chongqing Medical University; Xiaojing Lin, Chongqing Medical University; Jeff Sands, Emory University
• Language: English
• Date: 2019-10-01
• Publisher: Elsevier Inc.
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ebiom.2019.09.049
• Title of Journal or Parent Work: Ebiomedicine
• Volume: 48
• Start Page: 478
• End Page: 490
• Grant/Funding Information: This work was supported by NIH R01HD072074, National Natural Science Foundation of China grants 81770738, 81620108029 and 81330074, International Science & Technology Cooperation Program of China grant 2012DFA11070, the 111 Project, the Scientific and Technological Research Program of Chongqing Yuzhongqu Scientific and Technological Commission (20120202), Research Program of Chongqing National Health and Family Planning Commission (2012-1-038), and the Chongqing Science and Technology Commission (Project No. cstc2015jcyjA10036).
• Keywords: Life Sciences & Biomedicine; Medicine, Research & Experimental; Medicine, General & Internal; mTOR; Science & Technology; ACTIVATION; Carbamylation; Depression; LTP; SYNAPTIC PLASTICITY; PROTEINS; Urea; Research & Experimental Medicine; MICE LACKING; CONCENTRATING DEFECT; STRESS; PREVALENCE; PREFRONTAL CORTEX; PATHWAY; CHRONIC KIDNEY-DISEASE; General & Internal Medicine
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

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. Findings: 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. Interpretation: 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.