Background:The Shenlian formula demonstrates therapeutic bmodelenefits for diabetic kidney disease(DKD).Yet,its effectiveness in mitigating renal interstitial fibrosis(RIF)and the pharmacological underpinnings remain ...Background:The Shenlian formula demonstrates therapeutic bmodelenefits for diabetic kidney disease(DKD).Yet,its effectiveness in mitigating renal interstitial fibrosis(RIF)and the pharmacological underpinnings remain to be elucidated.This investigation seeks to delineate some of the formula’s potential mechanisms via experimental validation.Methods:The study initiated by inducing a DKD in rats through unilateral nephrectomy combined with streptozotocin(STZ)administration and an advanced glycation end products-bovine serum albumin(AGE-BSA)induced DKD model in HK-2 cells to assess the Shenlian formula’s renal protective effects.Renal tissues underwent pathological and immunohistochemical staining to evaluate improvements in RIF.Mechanistic insights were further obtained through techniques such as Western Blot,immunofluorescence,co-immunoprecipitation,enzyme-linked immunosorbent assay(ELISA),and protein docking analyses.Results:Shenlian formula could enhance renal function,alleviate tubular damage,suppress epithelial-mesenchymal transition(EMT),reduce extracellular matrix(ECM)deposition,and thus decelerate RIF progression.It notably decreased the expression of markers associated with pyroptosis(NOD-,LRR-and pyrin domain-containing protein 3(NLRP3),apoptosis-associated speck-like protein containing a CARD(ASC),caspase1,cleaved-caspase1,gasdermin D(GSDMD),GSDMD-N,interleukin-18(IL-18),interleukin-1 beta(IL-1β)),effectively inhibiting renal cell pyroptosis.Moreover,the formula facilitated autophagy substrate(sequestosome 1(p62))degradation,efficiently restoring the autophagy pathway.It also modulated autophagy,impacting cell pyroptosis regulation.Conclusion:The Shenlian formula potentially inhibits cellular pyroptosis by modulating the autophagy pathway,thereby diminishing inflammation-induced renal injury and fibrosis.This finding suggests a novel therapeutic approach for managing DKD-induced fibrosis.展开更多
文摘糖尿病肾脏疾病(diabetic kidney disease,DKD)是一种进行性慢性糖尿病微血管并发症之一,为终末期肾病的主要原因。越来越多的证据表明,肾脏炎症在DKD发病中发挥至关重要的作用,其机制与炎症介质的过度激活相关。NLR家族pyrin域蛋白3(NLR family pyrin domain containing protein 3,NLRP3)炎症小体作为一种经典的炎症小体,可在细胞内组装成NLRP3多蛋白复合体。当机体接受内、外源性病原体或损伤时,NLRP3多蛋白复合体激发体内一系列炎症反应,促进炎症因子IL-1β、IL-18等释放,进而诱导DKD发生、发展。本文主要介绍了NLRP3炎症小体在NLRP3/Caspase-1/IL-1β通路介导的肾脏固有细胞(如肾小管上皮细胞、足细胞及系膜细胞等)异常及在DKD病理生理学反应中相关机制。除此之外,还讨论了天然黄酮类化合物作为可选择性靶向作用于肾脏内NLRP3炎性小体及其信号通路分子的候选药物在减缓炎症反应、减轻DKD症状方面的应用潜力。本文可为对DKD患者的科学管理治疗提供新思路。
基金supported by the National Natural Science Foundation of China(Grant No.82374382,82074361,82274293)school-level major project of Beijing University of Chinese Medicine(2023-JYB-JBZD-037)+1 种基金hospital-level project of Dongzhimen Hospital,Beijing University of Chinese Medicine(DZMG-XZYY-23002)Chinese Society of Traditional Chinese Medicine Practical Project(ZSL-003-02)。
文摘Background:The Shenlian formula demonstrates therapeutic bmodelenefits for diabetic kidney disease(DKD).Yet,its effectiveness in mitigating renal interstitial fibrosis(RIF)and the pharmacological underpinnings remain to be elucidated.This investigation seeks to delineate some of the formula’s potential mechanisms via experimental validation.Methods:The study initiated by inducing a DKD in rats through unilateral nephrectomy combined with streptozotocin(STZ)administration and an advanced glycation end products-bovine serum albumin(AGE-BSA)induced DKD model in HK-2 cells to assess the Shenlian formula’s renal protective effects.Renal tissues underwent pathological and immunohistochemical staining to evaluate improvements in RIF.Mechanistic insights were further obtained through techniques such as Western Blot,immunofluorescence,co-immunoprecipitation,enzyme-linked immunosorbent assay(ELISA),and protein docking analyses.Results:Shenlian formula could enhance renal function,alleviate tubular damage,suppress epithelial-mesenchymal transition(EMT),reduce extracellular matrix(ECM)deposition,and thus decelerate RIF progression.It notably decreased the expression of markers associated with pyroptosis(NOD-,LRR-and pyrin domain-containing protein 3(NLRP3),apoptosis-associated speck-like protein containing a CARD(ASC),caspase1,cleaved-caspase1,gasdermin D(GSDMD),GSDMD-N,interleukin-18(IL-18),interleukin-1 beta(IL-1β)),effectively inhibiting renal cell pyroptosis.Moreover,the formula facilitated autophagy substrate(sequestosome 1(p62))degradation,efficiently restoring the autophagy pathway.It also modulated autophagy,impacting cell pyroptosis regulation.Conclusion:The Shenlian formula potentially inhibits cellular pyroptosis by modulating the autophagy pathway,thereby diminishing inflammation-induced renal injury and fibrosis.This finding suggests a novel therapeutic approach for managing DKD-induced fibrosis.
