Targeting AQP4 Restores the Glymphatic System Impairment Attenuating the Chronic Kidney Disease Induced Neurological Injury
Shao-Ho Yuan1, Hsueh-Te Lee1, Chih-Ping Chung3, Yeh-Shiu Chu2
1Institute of Anatomy and Cell Biology, 2Institute of Brain Science, National Yang Ming Chiao Tung University, 3Department of Neurology, Taipei Veterans General Hospital
Objective:
To provide the new insights toward ameliorating chronic kidney disease induced encephalopathy.
Background:
Chronic kidney disease (CKD) is long-term irreversible kidney dysfunction that continuously influences the whole body, including the central nervous system. Clinical reports have indicated that CKD patients experience cognitive impairment, anxiety, and depression. Furthermore, pronounced astrogliosis has been observed in the brains of rodents with experimentally induced CKD. The water channel protein called AQP4 is mainly expressed in astrocyte end-feet surrounding the vessel. It facilitates the movement of CSF into the brain tissue and its clearance back into the perivascular space occupying the most crucial process in the glymphatic system. So far, the role of AQP4 within astrocytes in mediating CKD-induced encephalopathy remains to be determined.
Design/Methods:
We established the CKD mice model by feeding the mice with 0.2% adenine. We performed the open field, rotarod, elevated plus maze and Morris watermaze to investigate the mice behavior. We used immunohistochemistry staining and western blot for specific antigen information. Furthermore, we injected the tracer to evaluate the glymphatic system function.
Results:
We revealed that CKD leads to encephalopathy characterized by gliosis, neuroinflammation, reduced spine density, and alterations in neuronal structural protein. We also observed impaired behavior in CKD mice, including decreased locomotor activity, impaired motor coordination and cognitive deficits compared to vehicle mice. Most importantly, we identified alterations in AQP4 expression patterns within astrocytes, which contribute to glymphatic system dysfunction in CKD mice brains. However, the adverse brain impact of CKD was mitigated by administering the AQP4 inhibitor, TGN020, nasally including the decreased level of proinflammatory cytokines, gliosis and neuronal damage. Most of all, we demonstrated that TGN020 administration ameliorates glymphatic dysfunction and further restores cognitive function.
Conclusions:
Our findings highlight the detrimental effects of CKD on mice brain health providing the potential therapeutic target that AQP4 inhibition ameliorate the CKD-induced encephalopathy.
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