Backgrounds:Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease(CKD)leads to cognitive impairment.However,the underlying mechanism requires further investigation.Here...Backgrounds:Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease(CKD)leads to cognitive impairment.However,the underlying mechanism requires further investigation.Herein,a mouse model of CKD was established using conventional 5/6 nephrectomy.We aimed to examine the relationship between CKD and cognitive impairment and elucidate the underlying mechanisms.Methods:Cognitive behavior was assessed using the Morris water maze,novel object recognition test,and fear conditioning test.Further experiments were also conducted to investigate the underlying molecular mechanisms.Results:Our clinical data revealed a decrease in cognitive function among patients with CKD,accompanied by elevated plasma levels of pro-inflammatory cytokines.A positive correlation between cytokine concentrations and serum creatinine levels,as well as a significant positive correlation with cognitive dysfunction,were observed.Correlation analyzes demonstrated that hippocampal cytokine levels were positively correlated with serum creatinine levels and cognitive dysfunction in CKD model mice.Furthermore,20 mg/mL interleukin-6(IL-6)significantly decreased HT22 cell activity in vitro.Further,HT22 cells treated with IL-6 showed increased expression levels of toll-like receptor 4(TLR4)and myeloid differentiation primary response gene 88(MyD88),thereby inducing the nuclear factor kappa-B p65 inflammatory pathway and mitochondria-dependent apoptosis.The CKD mouse model showed increased expression of TLR4 and cytokines in the hippocampus.TLR4 knockdown antagonized the IL-6-mediated pro-inflammatory and pro-apoptotic effects in HT22 cells.TLR4 knockdown in the CKD model mice decreased hippocampal inflammation and increased the number of neuron dendrites,thus ameliorated cognitive impairment.Conclusion:These results suggest that IL-6 triggers TLR4 activation to induce neuroinflammation and neurodegeneration in CKD,ultimately culminate in cognitive impairment.展开更多
基金Zhejiang Provincial Outstanding Youth Science Foundation,Grant/Award Numbers:2023C35009,LTGY23H050003,LTGY24H050004Scienceand Technology Plan Project of Wenzhou Municipality,Grant/Award Numbers:Y2020024,Y20210162,Y2023065Wenzhou Medical University,Grant/Award Number:XY2022007。
文摘Backgrounds:Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease(CKD)leads to cognitive impairment.However,the underlying mechanism requires further investigation.Herein,a mouse model of CKD was established using conventional 5/6 nephrectomy.We aimed to examine the relationship between CKD and cognitive impairment and elucidate the underlying mechanisms.Methods:Cognitive behavior was assessed using the Morris water maze,novel object recognition test,and fear conditioning test.Further experiments were also conducted to investigate the underlying molecular mechanisms.Results:Our clinical data revealed a decrease in cognitive function among patients with CKD,accompanied by elevated plasma levels of pro-inflammatory cytokines.A positive correlation between cytokine concentrations and serum creatinine levels,as well as a significant positive correlation with cognitive dysfunction,were observed.Correlation analyzes demonstrated that hippocampal cytokine levels were positively correlated with serum creatinine levels and cognitive dysfunction in CKD model mice.Furthermore,20 mg/mL interleukin-6(IL-6)significantly decreased HT22 cell activity in vitro.Further,HT22 cells treated with IL-6 showed increased expression levels of toll-like receptor 4(TLR4)and myeloid differentiation primary response gene 88(MyD88),thereby inducing the nuclear factor kappa-B p65 inflammatory pathway and mitochondria-dependent apoptosis.The CKD mouse model showed increased expression of TLR4 and cytokines in the hippocampus.TLR4 knockdown antagonized the IL-6-mediated pro-inflammatory and pro-apoptotic effects in HT22 cells.TLR4 knockdown in the CKD model mice decreased hippocampal inflammation and increased the number of neuron dendrites,thus ameliorated cognitive impairment.Conclusion:These results suggest that IL-6 triggers TLR4 activation to induce neuroinflammation and neurodegeneration in CKD,ultimately culminate in cognitive impairment.
