| Title | High urea induces depression and LTP impairment through mTOR signalling suppression caused by carbamylation |
| Authors | Wang, Hongkai Huang, Boyue Wang, Weiling Li, Jinfang Chen, Yi Flynn, Trevor Zhao, Meng Zhou, Zhiming Lin, Xiaojing Zhang, Yinan Xu, Mengmeng Li, Keqiong Tian, Kuan Yuan, Dezhi Zhou, Peng Hu, Ling Zhong, Dandan Zhu, Shuai Li, Jing Chen, Dilong Wang, Kejian Liang, Jianhui He, Qihua Sun, Jianbin Shi, Jie Yan, Li Sands, Jeff M. Xie, Zhengwei Lian, Xuemei Xu, Duan Ran, Jianhua Yang, Baoxue |
| Affiliation | Peking Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing, Peoples R China Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing, Peoples R China Chongqing Med Univ, Basic Med Coll, Dept Anat, Chongqing, Peoples R China Chongqing Med Univ, Basic Med Coll, Lab Neurosci & Tissue Engn, Chongqing, Peoples R China Chongqing Med Univ, Dept Neurol, Affiliated Hosp 2, Chongqing, Peoples R China Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA Chongqing Med Univ, Dept Radiol, Affiliated Hosp 2, Chongqing, Peoples R China Chongqing Med Univ, Res Ctr Med & Social Dev, Innovat Ctr Social Risk Governance Hlth, Sch Publ Hlth & Management, Chongqing, Peoples R China Peking Univ, Natl Inst Drug Dependence, Beijing, Peoples R China Chongqing Canc Res Inst, Chongqing, Peoples R China Chongqing Three Gorges Med Coll, Chongqing, Peoples R China Peking Univ, Ctr Med & Hlth Anal, Beijing, Peoples R China Peking Univ, Clin Lab, Hosp 3, Beijing, Peoples R China Ion Channel Explorer Biosci INC, Beijing, Peoples R China Emory Univ, Sch Med, Dept Med, Renal Div, Atlanta, GA USA Emory Univ, Sch Med, Dept Physiol, Renal Div, Atlanta, GA 30322 USA |
| Keywords | Urea Depression LTP Carbamylation mTOR |
| Issue Date | 2019 |
| Publisher | EBIOMEDICINE |
| 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 anddepression-like behaviour. CKD patients may be able to attenuate depression only by strict management of blood urea. (C) 2019 The Authors. Published by Elsevier B.V. |
| URI | http://hdl.handle.net/20.500.11897/553440 |
| ISSN | 2352-3964 |
| DOI | 10.1016/j.ebiom.2019.09.049 |
| Indexed | SCI(E) EI |
| Appears in Collections: | 基础医学院 天然药物与仿生药物国家重点实验室 第三医院 |
