Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China 325015.
Transplantation Centre, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China 325015.
Biomed Res Int. 2021 Jun 10;2021:6636621. doi: 10.1155/2021/6636621. eCollection 2021.
To observe the protective effect of AC-YVAD-CMK on sepsis-induced acute kidney injury in mice and to explore its possible mechanisms primarily.
Eighteen male C57BL/6 mice were randomly divided into sham-operated group (Control), cecal ligation and puncture group (CLP), and CLP model treated with AC-YVAD-CMK group (AC-YVAD-CMK) ( = 6 in each group). Mice were sacrificed at 24 h after operation, and blood and kidney tissue samples were collected for analyses. Histologic changes were determined microscopically following HE staining. The expression of Ly-6B and CD68 was investigated using immunohistochemistry. Serum concentrations of creatinine (sCR) and blood urea nitrogen (BUN) were measured. Serum levels of interleukin-1 (IL-1), interleukin-18 (IL-18), TNF-, and interleukin-6 (IL-6) were determined by ELISA. The expressions of Caspas-1, NLRP-1, IL-1, and IL-18 in renal tissues were investigated using Western blot. Immunofluorescence staining was used to detect the expression of GSDMD protein in renal tissues.
AC-YVAD-CMK treatment significantly alleviates sepsis-induced acute kidney injury, with decreased histological injury in renal tissues, suppresses the accumulation of neutrophils and macrophages in renal tissues, and decreased sCR and BUN level ( < 0.05). Attenuation of sepsis-induced acute kidney injury was due to the prohibited production of inflammatory cytokines and decrease expression of Caspas-1, NLRP-1, IL-1, and IL-18 in renal tissues. In addition, AC-YVAD-CMK treatment significantly reduced the expression of GSDMD in renal tissues compared to those observed in controls ( < 0.05).
We demonstrated a marked renoprotective effect of caspase-1-inhibitor AC-YVAD-CMK in a rat model of sepsis by inhibition of pyroptosis.
观察 AC-YVAD-CMK 对脓毒症诱导的小鼠急性肾损伤的保护作用，并初步探讨其可能的机制。
将 18 只雄性 C57BL/6 小鼠随机分为假手术组（对照）、盲肠结扎穿孔组（CLP）和 CLP 模型用 AC-YVAD-CMK 处理组（AC-YVAD-CMK）（每组 6 只）。术后 24 小时处死小鼠，采集血液和肾组织样本进行分析。采用 HE 染色观察组织学变化。采用免疫组织化学法检测 Ly-6B 和 CD68 的表达。检测血清肌酐（sCR）和血尿素氮（BUN）浓度。采用 ELISA 法检测血清白细胞介素-1（IL-1）、白细胞介素-18（IL-18）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平。采用 Western blot 法检测肾组织 Caspas-1、NLRP-1、IL-1 和 IL-18 的表达。采用免疫荧光染色检测肾组织 GSDMD 蛋白的表达。
AC-YVAD-CMK 治疗可显著减轻脓毒症诱导的急性肾损伤，减轻肾组织的组织学损伤，抑制肾组织中性粒细胞和巨噬细胞的聚集，并降低 sCR 和 BUN 水平（ < 0.05）。脓毒症诱导的急性肾损伤的减轻是由于抑制了炎症细胞因子的产生和 Caspas-1、NLRP-1、IL-1 和 IL-18 在肾组织中的表达。此外，与对照组相比，AC-YVAD-CMK 治疗可显著降低肾组织中 GSDMD 的表达（ < 0.05）。
我们通过抑制细胞焦亡，在脓毒症大鼠模型中证实了 caspase-1 抑制剂 AC-YVAD-CMK 具有显著的肾保护作用。
