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Correspondence; Jianhua Ran: ranjianhua@cqmu.edu.cn

Baoxue Yang: Baoxue@bjmu.edu.cn

Hongkai Wang, Boyue Huang, and Weiling Wang contributed equally to this work.

Hongkai Wang: Conceptualization, Data curation, Formal analysis, Writing - original draft.

Boyue Huang: Formal analysis, Writing - review & editing.

Weiling Wang: Data curation.

Jinfang Li: . Yi Chen: . Trevor Flynn: Data curation, Formal analysis.

Meng Zhao: . Zhiming Zhou: . Xiaojing Lin: . Yinan Zhang: . Mengmeng Xu: . Keqiong Li: Data curation.

Kuan Tian: . Dezhi Yuan: . Peng Zhou: . Ling Hu: . Dandan Zhong: . Shuai Zhu: . Jing Li: . Dilong Chen: . Kejian Wang: . Jianhui Liang: . Qihua He: . Jianbin Sun: . Jie Shi: . Li Yan: Data curation.

Jeff M Sands: . Zhengwei Xie: . Xuemei Lian: . Duan Xu: . Jianhua Ran: Conceptualization, Funding acquisition, Supervision, Writing - review & editing.

Baoxue Yang: Conceptualization, Funding acquisition, Supervision, Writing - review & editing.

The authors would like to thank Dr. Daqi Yu from School of Physics, Tianyu Zhang from School of Life Sciences, Bing Cao from School of Public Health, Peking University, Jingwei Song from Department of Statistics, University of California Los Angeles for enlightening conversation; Jingjie Li from Xi'an Jiaotong University, Junkui Shang from Capital Medical University, Chenyu Zhang and senior technician Mrs. Wenyuan Guo from School of Basic Medical Sciences, Peking University, Beian Dong and Yujiao Dou from Ion Channel Explorer Bioscience INC., Dr. Xingyu Zhang and Dr. Qiang Liu from the First People's Hospital of Chongqing Liang Jiang New Area for technologic assistance.

The authors declare no competing interests.

Funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript and eventually in the decision to submit the manuscript.


Research Funding:

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).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, General & Internal
  • Medicine, Research & Experimental
  • General & Internal Medicine
  • Research & Experimental Medicine
  • Urea
  • Depression
  • LTP
  • Carbamylation
  • mTOR

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

Journal Title:



Volume 48


, Pages 478-490

Type of Work:

Article | Final Publisher PDF


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.

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© 2019 The Authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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