中国中药杂志2026，Vol.51Issue(3)：693-707,15.DOI:10.19540/j.cnki.cjcmm.20251104.902
参芪地黄汤加味方调控脂代谢紊乱介导的脂滴积聚和TLR4/MyD88/NF-κB通路改善糖尿病肾脏疾病足细胞焦亡的作用和机制
Effects and mechanisms of Supplemented Shenqi Dihuang Decoction Formula in improving podocyte pyroptosis in diabetic kidney disease by regulating dyslipidemia-mediated lipid droplet accumulation and TLR4/MyD88/NF-κB pathway
摘要
Abstract
This study aimed to investigate the effects and mechanisms of the Supplemented Shenqi Dihuang Decoction Formula(SSDDF)in improving podocyte pyroptosis in diabetic kidney disease(DKD)by regulating dyslipidemia-mediated lipid droplet accumulation and the Toll-like receptor 4(TLR4)/myeloid differentiation primary response gene 88(MyD88)/nuclear factor-κB(NF-κB)signaling pathway.First,a modified DKD rat model was established.After successful modeling,the DKD rats were administered low-dose SSDDF(SSDDF-L),high-dose SSDDF(SSDDF-H),dapagliflozin(DAPA),or saline(vehicle)by gavage for six consecutive weeks.In the in vivo study,the general condition of the rats,blood glucose(BG),urinary albumin(UAlb),liver and renal function indexes,blood lipid profiles,and serum short-chain fatty acid(SCFA)levels were examined.Glomerular histopathological features,podocyte foot process morphology,and glomerular basement membrane(GBM)ultrastructure were compared.The protein expression levels of podocyte slit diaphragm structural molecules(nephrin and podocin)in renal tissue,key signaling molecules of the TLR4/MyD88/NF-κB pathway[TLR4,MyD88,phosphorylated inhibitor of NF-κBα(p-IκBα),and phosphorylated NF-κB p65(p-p65)],key molecules of the classical pyroptosis pathway[NOD-like receptor thermal protein domain-associated protein 3(NLRP3),apoptosis-associated speck-like protein containing a CARD(ASC),cleaved-caspase-1,and gasdermin D-N(GSDMD-N)],and effector inflammatory factors[interleukin-1β(IL-1β)and interleukin-18(IL-18)]were analyzed.Second,in the in vitro study,a lipotoxic podocyte injury model was constructed by treating MPC-5 cells with high glucose(HG)and palmitic acid(PA).The injured cells were then treated with either SSDDF-H-containing serum or the TLR4 inhibitor TAK-242.The lipid droplet characteristics and the expression levels of proteins associated with the TLR4/MyD88/NF-κB pathway and pyroptosis in podocytes were observed and analyzed.Additionally,in the network pharmacology study,potential targets of SSDDF and DKD were predicted and screened using the HERB and SwissTargetPrediction databases,and a"drug-component-target network"of SSDDF was constructed.DKD-related targets were integrated from the OMIM,GeneCards,and TTD databases.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses for the intersecting targets were performed using the DAVID database.Molecular docking was performed between the core components of SSDDF and key targets.The network pharmacology results suggested that the therapeutic effects of SSDDF on DKD were likely related to the regulation of lipid metabolism and inflammation-related signaling pathways.The in vivo results showed that SSDDF-L and SSDDF-H improved,to varying degrees,the general condition and the levels of BG,UAlb,serum creatinine(Scr),blood urea nitrogen(BUN),total cholesterol(TC),triglyceride(TG),the ratio of low-density lipoprotein cholesterol(LDL-C)to high-density lipoprotein cholesterol(HDL-C),and SCFA in DKD rats,ameliorated glomerular histopathological changes and podocyte ultrastructure,and improved renal protein expression levels of nephrin,podocin,TLR4,MyD88,p-IκBα,p-p65,NLRP3,ASC,cleaved caspase-1,GSDMD-N,IL-1β,and IL-18.Notably,regarding the improvement of proteinuria in the modified DKD rats,SSDDF was less effective than DAPA.However,for renal function and SCFA levels,SSDDF-H was superior to DAPA,and for blood lipid regulation,glomerulosclerosis,and podocyte injury,SSDDF showed similar efficacy to DAPA.The in vitro results showed that both SSDDF-H-containing serum and the TLR4 inhibitor reduced lipid droplet accumulation,inhibited TLR4/MyD88/NF-κB pathway activation,and alleviated podocyte pyroptosis,with comparable effects.In conclusion,SSDDF ameliorates podocyte pyroptosis in DKD by regulating dyslipidemia-mediated lipid droplet accumulation and the TLR4/MyD88/NF-κB signaling pathway.These findings provide pharmacological evidence for precisely elucidating the scientific connotation of the Jinling school's therapeutic approach to"Shenxiao disease".关键词
参芪地黄汤加味方/糖尿病肾脏疾病/脂毒性肾损伤/TLR4/MyD88/NF-κB通路/足细胞焦亡Key words
Supplemented Shenqi Dihuang Decoction Formula/diabetic kidney disease/lipotoxicity-induced kidney injury/TLR4/MyD88/NF-κB pathway/podocyte pyroptosis引用本文复制引用
沈昊雯,桑天庆,CHONG Fee-lan,许新梅,万毅刚,陈萍,李雅静,刘莹露,吴薇,房其军,何其函..参芪地黄汤加味方调控脂代谢紊乱介导的脂滴积聚和TLR4/MyD88/NF-κB通路改善糖尿病肾脏疾病足细胞焦亡的作用和机制[J].中国中药杂志,2026,51(3):693-707,15.基金项目
国家自然科学基金面上项目(82374364) （82374364）
国家自然科学基金青年基金项目(82505305) （82505305）
国家中医药管理局重大疑难疾病中西医临床协作项目(国中医药综结合发[2024-3号]-92) （国中医药综结合发[2024-3号]-92）
江苏省自然科学基金面上项目(BK20231123) （BK20231123）
江苏省中医药领军人才培养项目(SLJ0301) （SLJ0301）
江苏省自然科学基金青年项目(SBK20250402581) （SBK20250402581）
南京市医学科技发展项目(ZKX24015,YKK24077) （ZKX24015,YKK24077）
南京市中医药青年人才培养计划项目(ZYQ20066) （ZYQ20066）
南京鼓楼医院临床研究专项资金项目(2024-LCYJ-ZXY-01) （2024-LCYJ-ZXY-01）
