High urea induces anxiety disorders associated with chronic kidney disease by promoting abnormal proliferation of OPC in amygdala

Boyue Huang; Zhizhen Huang; Hongkai Wang; Guoqi Zhu; Hui Liao; Zhiwen Wang; Baoxue Yang; Jianhua Ran

doi:10.1016/j.ejphar.2023.175905

High urea induces anxiety disorders associated with chronic kidney disease by promoting abnormal proliferation of OPC in amygdala

Eur J Pharmacol. 2023 Oct 15:957:175905. doi: 10.1016/j.ejphar.2023.175905. Epub 2023 Aug 26.

Authors

Boyue Huang¹, Zhizhen Huang², Hongkai Wang³, Guoqi Zhu⁴, Hui Liao⁴, Zhiwen Wang⁴, Baoxue Yang⁵, Jianhua Ran⁶

Affiliations

¹ Department of Anatomy and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China; Department of Pharmacology, School of Basic Medical Sciences, And State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
² Department of Pharmacology, School of Basic Medical Sciences, And State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
³ Laboratory of Regenerative Rehabilitation, Shirley Ryan Ability Lab, Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine 2 Northwestern University Interdepartmental Neuroscience Program, USA.
⁴ Department of Anatomy and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China.
⁵ Department of Pharmacology, School of Basic Medical Sciences, And State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. Electronic address: baoxue@bjmu.edu.cn.
⁶ Department of Anatomy and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China; Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China. Electronic address: ranjianhua@cqmu.edu.cn.

PMID: 37640220
DOI: 10.1016/j.ejphar.2023.175905

Abstract

Chronic kidney disease (CKD) with anxiety disorder is of a great concern due to its high morbidity and mortality. Urea, as an important toxin in CKD, is not only a pathological factor for complications in patients with CKD, but also is accumulated in the brain of aging and neurodegenerative diseases. However, the pathological role and underlying regulatory mechanism of urea in CKD related mood disorders have not been well established. We previously reported a depression phenotype in mice with abnormal urea metabolism. Since patients with depression are more likely to suffer from anxiety, we speculate that high urea may be an important factor causing anxiety in CKD patients. In adenine-induced CKD mouse model and UT-B^-/- mouse model, multiple behavioral studies confirmed that high urea induces anxiety-like behavior. Single-cell transcriptome revealed that down-regulation of Egr1 induced compensatory proliferation of oligodendrocyte progenitor cells (OPC). Myelin-related signaling pathways of oligodendrocytes (OL) were change significant in the urea accumulation amygdala. The study showed that high urea downregulated Egr1 with subsequent upregulation of ERK pathways in OPCs. These data indicate that the pathological role and molecular mechanism of high urea in CKD-related anxiety, and provide objective serological indicator and a potential new drug target for the prevention and treatment of anxiety in CKD patients.

Keywords: Amygdala; Anxiety; Chronic kidney disease; Oligodendrocytes; Urea.

MeSH terms

Amygdala
Animals
Anxiety / complications
Anxiety Disorders / complications
Cell Proliferation
Humans
Mice
Oligodendrocyte Precursor Cells*