GSDMD介导细胞焦亡缓解高尿酸血症小鼠肾损伤的作用机制  

Mechanism of gasdermin D protein-mediated pyroptosis in alleviating kidney injury of mice induced by hyperuricemia

作　　者：马丽莎 申瑞芹 焦杰 罗浩[1] 徐爱萍 邵德翠[1] MA Lisha;SHEN Ruiqin;JIAO Jie;LUO Hao;XU Aiping;SHAO Decui(Cell Electrophysiology Laboratory,Wannan Medical College,Wuhu 241002,Anhui,China)

机构地区：[1]皖南医学院细胞电生理研究室,安徽芜湖241002

出　　处：《皖南医学院学报》2024年第1期5-8,共4页Journal of Wannan Medical College

基　　金：安徽高校自然科学研究项目(2022AH040173,20022AH051245)。

摘　　要：目的:探讨gasdermin D蛋白(GSDMD)在高尿酸血症(HUA)后肾损伤中的作用及其可能机制。方法:选用C57BL/6J的野生型小鼠和GSDMD敲除小鼠作为实验动物,将其分为4组,野生型小鼠正常饮食组(WT-Norm-diet组),野生型小鼠高尿酸造模组(WT-HUA组),GSDMD敲除小鼠正常饮食组(KO-Norm-diet组)和GSDMD敲除小鼠高尿酸造模组(KO-HUA组)。HUA动物造模选用氧嗪酸钾[250 mg/(kg·d)]和腺嘌呤[50 mg/(kg·d)]对小鼠灌胃28 d;血生化检测肌酐和尿酸变化;HE染色观察肾脏病理学变化;Western blot检测肾皮质GSDMD、GSDMD-N的蛋白表达;RT-PCR检测KIM-1和NAGL的表达量。结果:与WT-Norm-diet组比较,WT-HUA组小鼠血清中尿酸升高(P<0.01);肾皮质中GSDMD、GSDMD-N的蛋白表达水平升高(P<0.05);KIM-1 mRNA的表达水平升高(P<0.01)。与WT-HUA组比较,KO-HUA组小鼠血清尿酸、肌酐水平、NAGL mRNA表达降低(P<0.05)。HE染色结果显示,KO-HUA组小鼠高尿酸导致的肾小管扩展以及炎性细胞浸润明显改善。结论:GSDMD敲除可有效缓解高尿酸引起的肾脏损伤。Objective:To investigate the role and mechanism of pyroptosis execution gasdermin D protein(GSDMD)in alleviating the kidney injury of mice induced by hyperuricemia(HUA).Methods:C57BL/6J WT and GSDMD knockout mice were selected as experimental animals,and divided into groups of WT-Norm-diet,WT-HUA,KO-Norm-diet and KO-HUA.Potassium oxonate(250 mg/(kg·day))and adenine(50 mg/(kg·day))were administered by gavage for 28 days to establish the HUA model.Blood was collected to measure the uric acid and creatinine levels.Hematoxylin and eosin(HE)staining was used to observe tissue morphological changes.The expressions of GSDMD and GSDMD-N in renal cortex were measured by Western blot.KIM-1 and NAGL mRNA levels were determined by RT-PCR.Results:Compared with the WT-Norm-diet group,the serum levels of uric acid were higher in the WT-HUA group(P<0.01).Western blot results showed that the GSDMD and GSDMD-N protein level were significantly increased in the WT-HUA group compared with the WT-Norm-diet group(P<0.01).RT-PCR revealed that KIM-1 mRNA level was significantly up-regulated in the WT-HUA group(P<0.01).Compared with the WT-HUA group,the serum levels of uric acid,creatinine and NAGL mRNA expression were significantly lower in KO-HUA group(P<0.05).The HE exhibited tubular necrosis,tubular extension and inflammatory cell infiltration in the kidney tissues in mice from the WT-HUA group,yet reduced tubular damage in the KO-HUA group.Conclusion:GSDMD knockout can effectively mitigate the kidney injury caused by hyperuricemia.

关 键 词：高尿酸血症 肾损伤 细胞焦亡 gasdermin D蛋白 

分 类 号：R-332[医药卫生] R