The Effect And Molecular Mechanisms Of Exercise On Diabetic Depression Based On KLK8

Objective:Depression,the most common psychiatric complication of diabetes,is affecting20-40% of diabetic patients and is a clinical problem that deserves high priority.But the mechanisms involved are still unclear.Inflammatory factor aggregation may be one of the mechanisms that promote the course of diabetes and simultaneously cause damage to the central nervous system.The involvement of Kallikrein8 in the development and regulation of depression-like behavior has been demonstrated,and exercise anti-inflammation is also an effective way to treat depression.Therefore,the purpose of this study was to confirm that KLK8 is indeed involved in diabetic depression-like behavior,and on this basis,to observe the involvement of KLK8 in the pathogenesis of diabetic depression through the activation of related inflammatory pathways.Finally to investigate whether exercise can improve the symptoms of diabetic depression through the above molecular mechanisms.Methods:At the overall level,C57BL/6 mice,KLK8 knockout mice and exercise mice were grouped,and the diabetic group was injected with STZ to construct a 4-week type I diabetes model.The mice in the exercise group were simultaneously subjected to a 4-week running platform exercise.4 weeks later,the mice were tested for depressive behavior,and hippocampal tissues were taken for Western Blot,q PCR,and immunofluorescence to analyze the expression of related proteins,inflammatory factor m RNA,and microglia activation.At the cellular level,BV-2 microglia were used for low glucose(5 m M)and high glucose(25 m M)culture to simulate in vitro diabetes levels.Cells were taken for Western Blot and q PCR after adenovirus transfection and si RNA transfection interventions to analyze the m RNA expression of related proteins and inflammatory factors.Results:First,we found that KLK8 was upregulated in diabetes by gene microarray analysis,and subsequently verified this result by Western Blot and q PCR of hippocampal tissue.Then,KLK8 knockdown showed a significant improvement in diabetes-induced depression-like behavior and was able to inhibit microglia activation and reduce hippocampal inflammatory factor expression.The cellular results also showed that KLK8 overexpression dose-dependently promoted microglia activation and inflammatory factor expression,whereas KLK8 knockdown suppressed both microglia activation and inflammatory factor expression.To find the inflammatory signaling pathways associated with depression,we used GSEA enrichment analysis and found that KLK8 upregulation activated the IL-6/ JAK/ STAT signaling pathway.In contrast,exercise significantly downregulated KLK8 expression,which inhibited this pathway,suppressed microglia activation,reduced inflammatory responses in the hippocampus,and improved depression-like behavior.Conclusion:The Kallikrein8-driven hippocampal inflammatory response is key to diabetesinduced depression-like behavior,and upregulation of a large number of inflammatory factors in hippocampal tissue activates the IL-6/ JAK/ STAT signaling pathway,which affects diabetes-complicated depression.In contrast,moderate intensity aerobic training can reduce KLK8 expression in vivo,inhibit microglia activation,reduce the inflammatory response in the hippocampus,and improve depression-like behaviors by inhibiting this pathway.