数字中医药（英文）2025，Vol.8Issue(3)：379-388,10.DOI:10.1016/j.dcmed.2025.09.009
左归降糖益肾方调控NLRP3/caspase-1/GSDMD信号轴对糖尿病肾病大鼠细胞焦亡的影响
Effects of Zuogui Jiangtang Yishen Formula in regulating the NLRP3/caspase-1/GSDMD signaling axis on pyroptosis in rats with diabetic kidney disease
摘要
Abstract
Objective To investigate the effects of Zuogui Jiangtang Yishen Formula(左归降糖益肾方,ZGJTYSF)in regulating the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)/caspase-1/gasdermin D(GSDMD)signaling axis on pyroptosis in rats with diabet-ic kidney disease(DKD). Methods Fifty male specific pathogen-free(SPF)grade Goto-Kakizaki(GK)rats(12 weeks old)were fed a high-fat diet for one month to establish an early DKD model.Model establish-ment was confirmed when fasting blood glucose(FBG)≥11.1 mmol/L and urinary albumin-to-creatinine ratio(uACR)≥30 mg/g.The successfully modeled early DKD rats were ran-domly divided by random number table into five groups(n=10 per group):model group;da-pagliflozin group(1.0 mg/kg,by gavage,served as positive control);and low-,medium-,and high-dose of ZGJTYSF groups(4.9,9.9,and 19.9 g/kg,respectively,by gavage).Age-matched male SPF Wistar rats(n=10)served as control group.Rats in control and model groups were gavaged with equivalent volumes of distilled water.Treatment lasted 12 weeks.Changes in uACR,FBG,and renal function were observed in all groups.Hematoxylin-eosin(HE),period-ic acid-Schiff(PAS),and Masson staining were used to observe renal histopathological changes.Immunohistochemistry was performed to detect the localization and expression of caspase-1,GSDMD,and NLRP3 in rat renal tissues.Terminal deoxynucleotidyl transferase deoxyuridine triphosphate(dUTP)nick end labeling(TUNEL)was utilized to detect pyropto-sis in renal tissues.Quantitative real-time polymerase chain reaction(qPCR)and Western blot were applied to detect mRNA and protein expression levels of NLRP3,caspase-1,GSD-MD,interleukin(IL)-1β,and IL-18. Results Compared with model group,all doses of ZGJTYSF showed reductions in FBG,with medium-and high-dose of ZGJTYSF groups demonstrating significant decreases at week 8 and 12(P<0.05).For uACR,all doses of ZGJTYSF groups exhibited a decreasing trend,with high-dose of ZGJTYSF group being significantly lower than low-and medium-dose of ZGJ-TYSF groups at week 12(P<0.05)and showing no significant difference from dapagliflozin group(P>0.05).No significant differences in renal function parameters(serum creatinine,blood urea nitrogen,and uric acid)were observed among groups(P>0.05).Histopathologi-cal examination revealed milder glomerular and tubular lesions in both ZGJTYSF groups and dapagliflozin group,with renal pathological changes in high-dose of ZGJTYSF group resem-bling those in dapagliflozin group.Immunohistochemistry demonstrated significantly reduced expression of caspase-1,GSDMD,and NLRP3 in renal tissues of dapagliflozin group and high-dose of ZGJTYSF group compared with model group(P<0.05 or P<0.01),while the differences in low-and medium-dose of ZGJTYSF groups were not statistically significant(P>0.05).TUNEL assay showed significantly fewer TUNEL-positive cells in renal tissues of da-pagliflozin and high-dose of ZGJTYSF groups(P<0.01),indicating a marked reduction in py-roptotic cells.Molecular analysis revealed that compared with model group,both da-pagliflozin and high-dose of ZGJTYSF groups showed significantly downregulated mRNA and protein expression levels of NLRP3,caspase-1,GSDMD,IL-1β,and IL-18 in renal tissues(P<0.01),while low-and medium-dose of ZGJTYSF groups showed downward trends without sta-tistical significance(P>0.05). Conclusion ZGJTYSF may inhibit renal pyroptosis by regulating the NLRP3/caspase-1/GSDMD signaling axis,thereby preventing and treating early renal injury in DKD and delay-ing the onset and progression of DKD.关键词
左归降糖益肾方/糖尿病肾病/NLRP3/caspase-1/GSDMD信号轴/细胞焦亡/GK大鼠Key words
Zuogui Jiangtang Yishen Formula(左归降糖益肾方)/Diabetic kidney disease/NLRP3/caspase-1/GSDMD signaling axis/Pyroptosis/Goto-Kakizaki(GK)rats引用本文复制引用
胡淑娟,李旭华,刘秀,彭瑶,陈莉莉,喻嵘,彭亚军..左归降糖益肾方调控NLRP3/caspase-1/GSDMD信号轴对糖尿病肾病大鼠细胞焦亡的影响[J].数字中医药（英文）,2025,8(3):379-388,10.基金项目
National Natural Science Foundation of China(U21A20411),Innovative Research Group Program of Hu-nan Provincial Natural Science Foundation(2024JJ1007),and Hunan Provincial Natural Science Foundation(2023JJ30473). （U21A20411）
