Research Paper Volume 13, Issue 5 pp 6681—6701
Indoxyl sulfate caused behavioral abnormality and neurodegeneration in mice with unilateral nephrectomy
- 1 Department of Nephrology, Chang Gung Memorial Hospital, Keelung 204, Taiwan
- 2 Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung 204, Taiwan
- 3 Kidney Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- 4 School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- 5 Division of Urology, Taichung Veterans General Hospital, Taichung 407, Taiwan
- 6 Department of Family Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan
- 7 Institute of Clinical Medicine, National Yang Ming University, Taipei 112, Taiwan
- 8 Center for Geriatrics and Gerontology, Taichung Veterans General Hospital, Taichung 407, Taiwan
- 9 Department of Urology, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan
- 10 Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 104, Taiwan
- 11 Mackay Junior College of Medicine, Nursing and Management, Taipei 251, Taiwan
- 12 Children’s Medical Center, Taichung Veterans General Hospital, Taichung 407, Taiwan
- 13 Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung 407, Taiwan
- 14 Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan
- 15 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan
- 16 Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan
Received: August 3, 2020 Accepted: December 29, 2020 Published: February 17, 2021
https://doi.org/10.18632/aging.202523How to Cite
Copyright: © 2021 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Chronic Kidney Disease (CKD) and neurodegenerative diseases are aging-related diseases. CKD with declined renal function is associated with an elevation of circulating indoxyl sulfate, a metabolite synthesized by gut microbes. We explored the roles of gut microbial metabolites in linking with Central Nervous System (CNS) diseases by administrating indoxyl sulfate intraperitoneally to male C57BL/6 mice with unilateral nephrectomy. Upon exposure, the accumulation of indoxyl sulfate was noted in the blood, prefrontal cortical tissues, and cerebrospinal fluid. Mice showed behavioral signs of mood disorders and neurodegeneration such as anxiety, depression, and cognitive impairment. Those behavioral changes were accompanied by disturbed neuronal survival, neural stem cell activity, expression of Brain-Derived Neurotrophic Factor, serotonin, corticosterone, and Repressor Element-1 Silencing Transcription Factor, and post-receptor intracellular signaling, as well as upregulated oxidative stress and neuroinflammation. Uremic toxin adsorbent AST-120 improved the above mentioned changes. Intriguingly, intracerebroventricular indoxyl sulfate administration only caused limited alterations in the normal mice and the alterations were reversed by aryl hydrocarbon receptor antagonism. The findings suggest pathogenic roles of indoxyl sulfate in the development of CNS diseases, and highlight gut microbiota as alternative targets for intervention with the aim of slowing down the progression of CKD and decreasing CNS complications.