High urea induces depression and LTP impairment through mTOR signalling suppression caused by carbamylation
Hongkai Wang,
Boyue Huang,
Weiling Wang,
Jinfang Li,
Yi Chen,
Trevor Flynn,
Meng Zhao,
Zhiming Zhou,
Xiaojing Lin,
Yinan Zhang,
Mengmeng Xu,
Keqiong Li,
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,
Jeff M Sands,
Zhengwei Xie,
Xuemei Lian,
Duan Xu,
Jianhua Ran,
Baoxue Yang
Affiliations
Hongkai Wang
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; Department of Anatomy, and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China
Boyue Huang
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
Weiling Wang
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
Jinfang Li
Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
Yi Chen
Department of Anatomy, and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China
Trevor Flynn
Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA,
Meng Zhao
Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
Zhiming Zhou
Department of Radiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
Xiaojing Lin
School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
Yinan Zhang
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; National Institute on Drug Dependence, Peking University, Bejing, China
Mengmeng Xu
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
Keqiong Li
Chongqing Cancer Research Institute, Chongqing, China
Kuan Tian
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
Dezhi Yuan
Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
Peng Zhou
Department of Anatomy, and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China
Ling Hu
Department of Anatomy, and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China
Dandan Zhong
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
Shuai Zhu
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
Jing Li
Department of Anatomy, and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China
Dilong Chen
Department of Anatomy, and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China; Chongqing Three Gorges Medical College, Chongqing, China
Kejian Wang
Department of Anatomy, and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China
Jianhui Liang
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; National Institute on Drug Dependence, Peking University, Bejing, China
Qihua He
Center of Medical and Health Analysis, Peking University, Beijing, China
Jianbin Sun
Clinical Laboratory, Peking University Third Hospital, Beijing, China
Jie Shi
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; National Institute on Drug Dependence, Peking University, Bejing, China
Li Yan
Ion Channel Explorer Bioscience INC., Beijing, China
Jeff M Sands
Renal Division, Department of Medicine and Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA
Zhengwei Xie
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
Xuemei Lian
School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
Duan Xu
Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA,
Jianhua Ran
Department of Anatomy, and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China; Corresponding authors.
Baoxue Yang
Department of Pharmacology, School of Basic Medical Sciences, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; Corresponding authors.
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. Keywords: Urea, Depression, LTP, Carbamylation, mTOR
