Hsf1通过HSP70-TLR4-MyD88信号通路调控肾脏AA淀粉变

Hsf1 regulates renal amyloidosis via HSP70-TLR4-MyD88 signaling pathway

目的探讨HSP70-TLR4-MyD88信号通路在肾脏AA淀粉样变中的作用机制,以及Hsf1基因对其通路的调节作用。方法使用Hsf1基因敲除小鼠构建肾脏AA淀粉样变模型,以野生型小鼠为对照。模型制备成功后,从各组小鼠肾脏组织中提取mRNA进行检测评估;使用刚果红和免疫组化染色比较各组肾脏AA淀粉样物质的沉积程度。构建替普瑞酮(GGA)治疗组模型,对比治疗组与实验组肾脏淀粉样变情况。结果淀粉样变诱导试验后,Hsf1^(+/+)小鼠肾脏HSP70 mRNA表达量显著升高,而Hsf1^(-/-)小鼠肾脏组织HSP70 mRNA表达量无明显改变。Hsf1^(-/-)淀粉样变诱导组小鼠肾脏TLR4及下游因子MyD88以及细胞因子Tnf-α和IL-6的mRNA表达量均显著高于Hsf1^(+/+)淀粉样变诱导组小鼠。刚果红染色和免疫组化染色示:Hsf1^(-/-)淀粉样变诱导组肾脏淀粉样物质沉积程度明显高于Hsf1^(+/+)淀粉样变诱导组(P<0.01),其余生理盐水组肾脏未见淀粉样沉积。给予GGA治疗后,有效诱导了HSP70表达,从而抑制了炎症刺激后炎症因子的高表达,并一定程度上削弱了淀粉样变沉积程度。结论Hsf1通过调控HSP70-TLR4-MyD88信号通路有效抑制了肾脏AA淀粉样变,为淀粉样变疾病的临床预防与治疗提供了新思路。

Purpose To explore whether Hsf1 regulates renal amyloidosis via HSP70-TLR4-MyD88 signaling pathway.Methods Hsf1 knockout male mice were used to establish an AA amyloidosis model,and the wild-type mice were used as the control group.mRNA was extracted from the kidney tissue of mice in each group for detection and evaluation.Congo red and immunohistochemistry were used to compare the deposition of AA amyloid in the kidney of each group according to amyloid index.Moreover,the model of geranylgeranylacetone(GGA)treatment group was constructed,and the degree of renal amyloidosis was compared between the treatment group and the non-treatment group.Results After amyloid induction,the expression of HSP70 mRNA in the kidney of Hsf1^(+/+)mice was significantly increased,while there was almost no changed in Hsf1^(-/-) mice.The mRNA expression of TLR4,MyD88,Tnf-αand IL-6 in Hsf1^(-/-)amyloid induced group was significantly higher than those in Hsf1^(+/+)amyloid induced group.Congo red staining and immunohistochemical staining showed that the degree of amyloid deposition in the kidney of the Hsf1^(-/-)amyloid induced group was significantly higher than that of the Hsf1^(+/+)amyloid induced group(P<0.01).After GGA treatment,the expression of HSP70 was effectively enhanced in Hsf1^(-/-)amyloid induced group,which inhibited the expression of inflammatory factors,and ameliorated the amyloidosis deposition.Conclusion Hsf1 inhibits renal amyloidosis effectively by regulating HSP70-TLR4-MyD88 signaling pathway,which provides a new idea for clinical prevention and treatment of amyloidosis.