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.

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.