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目的研究特异性Caspaso-1抑制剂对狼疮性肾炎(LN)的治疗作用及其作用机制。方法应用特异性Caspase-1抑制剂AC-YVAD-CMK处理LN模型．BXSB小鼠4周,然后观察此潜在药物对该模型尿蛋白浓度、肾功能和血清自身抗体水平以及肾脏病理形态学的影响,继之检测它对。肾脏局部及全身系统Caspase-1活性以及其下游细胞因子IL-18和IFN-γ表达的影响。结果未治疗LN模型血清肌酐(Scr)、血清抗ds-DNA抗体水平以及尿蛋白浓度显著升高(P均<0．05);肾小球IgG沉积及肾小球病理损伤程度显著较对照小鼠严重(P均<0．005);肾脏及脾脏Caspase-1活性显著升高(P< 0．01),成熟形式IL-18蛋白表达升高(P<0．001),IFN-γmRNA表达显著上调(JP<0．05);血清IFT-γ水平也显著升高(P<0．01)。IcE抑制剂处理后Scr、抗ds-DNA抗体水平及尿蛋白浓度显著回降(P< 0．05);肾小球病理损伤较未处理组显著减轻(P<0．05),但肾小球IgG沉积差异无统计学意义(P> 0．05);肾脏及脾脏Caspase-1活性、成熟IL-18蛋白表达和IFN-γ mRNA表达均有不同程度回降(P均< 0．05),血清IFN-γ水平也显著回降(P<0．05)。结论选择性Caspase-1抑制剂对LN肾损伤具有良好的保护作用,抑制Caspase-1活性,进而抑制IL-18等细胞因子的活化和下游因子IFN-γ等的表达是其主要作用机制。
Objective To investigate the therapeutic effect and mechanism of specific Caspaso-1 inhibitor on lupus nephritis (LN). Methods LN model was treated with AC-YVAD-CMK, a specific Caspase-1 inhibitor. BXSB mice for 4 weeks, and then observe the potential drug on the model of urinary protein concentration, renal function and serum autoantibodies and renal pathological morphology, followed by testing it. Effects of local and systemic renal Caspase-1 activity and its downstream cytokines IL-18 and IFN-γ expression in kidney. Results Serum creatinine (Scr), serum anti-dsDNA antibody level and urinary protein concentration were significantly increased in untreated LN model group (all P <0.05). Glomerular IgG deposition and glomerular pathological damage were significantly lower than those in control (P <0.005). Caspase-1 activity in kidney and spleen was significantly increased (P <0.01), the expression of mature IL-18 protein was increased (P <0.001) (P <0.01). The serum level of IFT-γ was also significantly increased (P <0.01). Scr, anti-dsDNA antibody level and urinary protein concentration decreased significantly after IcE inhibitor treatment (P <0.05). Glomerular pathological changes were significantly reduced (P <0.05) (P <0.05). The activity of Caspase-1, the expression of mature IL-18 protein and the mRNA expression of IFN-γin kidney and spleen decreased to different extents (all P <0.05) , Serum IFN-γ levels also significantly decreased (P <0.05). CONCLUSION: Caspase-1 inhibitor has a protective effect on renal injury induced by LN and inhibits the activity of Caspase-1, and then inhibits the activation of cytokines such as IL-18 and the expression of downstream factor IFN-γ.