High urea promotes mitochondrial fission and functional impairments in astrocytes inducing anxiety-like behavior in chronic kidney disease mice.

High urea can induce depression and anxiety. Activation of astrocytes is closely associated with psychiatric disorders. However, the pathological mechanism of whether high urea affects astrocyte structure and function to induce anxiety-like behaviors remain unclear. We established a high-urea chronic kidney disease (CKD) mouse model and found that these mice exhibited elevated levels of anxiety through behavioral experiments. Immunofluorescence and transmission electron microscopy studies of astrocytes revealed a decrease in density and branching of mPFC astrocytes. Additionally, we observed a significant reduction in ATP and BDNF levels in the mPFC and primary astrocytes of CKD mice induced by high urea. Analysis of gene expression differences in astrocytes between WT and high-urea mice indicated alterations in mitochondrial dynamics-related signaling pathways in astrocytes. We established a high-urea primary astrocyte model to assess mitochondrial function and levels of fusion and fission proteins. Treatment of primary astrocytes with high urea led to mitochondrial fragmentation and downregulation of Mfn2 expression. These results suggested that high urea downregulates Mfn2 expression in mPFC astrocytes, induced mitochondrial fusion-fission abnormalities, disrupted astrocyte energy metabolism, and promoted high-urea-related anxiety. Mfn2 may represent a potential therapeutic target for high-urea-related anxiety.