基于内质网应激触发铁死亡探讨益气养阴活血方改善糖尿病肾病大鼠肾损伤的作用机制  

Exploring the Action Mechanism of Yiqi Yangyin Huoxue Formula Improving Renal Injury in Rats with Diabetic Nephropathy Based on Endoplasmic Reticulum Stress-triggered Ferroptosis

作　　者：方虹 宋纯东[1,2] 王旭[1,2] 樊艳敏 季晗舒 姜浩然 Fang Hong;Song Chundong;Wang Xu(Department of Pediatrics,First Af filiated Hospital of Henan University of Chinese Medicime,Zhengzhou 450099,China;College of Pediatrics.Henan University of Chinese Medicine,Zhengzhou 450046,China)

机构地区：[1]河南中医药大学第一附属医院儿科医院,郑州450099 [2]河南中医药大学儿科医学院,郑州450046

出　　处：《华中科技大学学报(医学版)》2025年第2期172-179,共8页Acta Medicinae Universitatis Scientiae et Technologiae Huazhong

基　　金：国家自然科学基金面上项目(No.82074493);河南省卫生健康委员会河南省中医药科学研究专项重点课题(No.2024ZY1002);河南省中医药学科领军人才项目[No.豫卫中医函(2021)8号];河南省中医药科学研究重大专项(No.2023ZYZD02)。

摘　　要：目的探讨益气养阴活血方改善糖尿病肾病(diabetic nephropathy,DN)大鼠肾损伤的机制。方法雄性SD大鼠采用高脂高糖饲料喂养联合单次腹腔注射链脲佐菌素建立DN模型,按随机数字表法分为模型组、缬沙坦组、益气养阴活血方等剂量(益等)组、益气养阴活血方高剂量(益高)组,从造模第10周起各治疗组灌胃给药,灌胃6周后检测各组大鼠24 h尿蛋白定量(24h-UTP)、尿素氮(BUN)、血肌酐(SCr)、葡萄糖(GLU)、总胆固醇(CHOL)、三酰甘油(TG);ELISA检测血清丙二醛(MDA)水平;Western blot检测大鼠肾组织XBP1、HRD1、Nrf2、SLC7A11、GPX4蛋白表达;qRT-PCR检测大鼠肾组织XBP1、HRD1、Nrf2、SLC7A11、GPX4 mRNA表达水平;HE染色观察各组大鼠肾组织病理学变化。结果模型组大鼠24h-UTP、BUN、SCr、GLU、CHOL、TG水平较正常对照均明显升高(均P<0.01),血清MDA水平显著升高(P<0.01),肾组织XBP1、HRD1蛋白及mRNA表达显著升高(均P<0.01),Nrf2、SLC7A11、GPX4蛋白及mRNA表达明显降低(均P<0.01),肾脏病理损伤严重。与模型组比较,缬沙坦组、益等组、益高组24h-UTP、BUN、SCr、GLU、CHOL、TG水平均显著降低(均P<0.01),血清MDA水平显著降低(P<0.01),肾组织XBP1、HRD1蛋白及mRNA表达明显降低(均P<0.01),Nrf2、SLC7A11、GPX4蛋白及mRNA表达显著升高(均P<0.01),肾脏病理得到改善。结论益气养阴活血方可能通过调节XBP1/HRD1/Nrf2信号通路抑制内质网应激的发生,减轻铁死亡损伤,保护肾功能,改善肾损伤。Objective To investigate the mechanism of improving renal injury in rats with diabetic nephropathy(DN)by Yiqi Yangyin Huoxue Formula.Methods Male SD rats were fed with high-fat and high-sugar diet,combining with a single intraperitoneal injection of streptozotocin to establish DN model.The rats were divided into the model group,the valsartan group,the equal-dose group of Yiqi Yangyin Huoxue Formula(equal-Yi group),and the high-dose group of Yiqi Yangyin Huoxue Formula(high-Yi group)according to the method of randomized numerical table.The treatment groups were administered by gavage from the tenth week of the modeling period.Levels of 24-hour urinary total protein(UTP),blood urea nitrogen(BUN),serum creatinine(SCr),glucose(GLU),cholesterol(CHOL),and triglycerides(TG)were measured.Serum malondialdehyde(MDA)levels were detected by ELISA.Western blot was used to detect the protein expression of XBP1,HRD1,Nrf2,SLC7A11,and GPX4 in rat kidney tissues.The qRT-PCR was used to detect the mRNA expression levels of XBP1,HRD1,Nrf2,SLC7A11,and GPX4 in rat kidney tissues.HE staining was used to observe the pathological changes in the kidney tissues of rats in each group.Results Compared with the blank group,rats in the model group showed significantly higher levels of 24h-UTP,BUN,SCr,GLU,CHOL,and TG(all P<0.01),significantly higher levels of serum MDA(P<0.01),significantly higher expression of XBP1,HRD1 protein and mRNA in renal tissues(all P<0.01),significantly lower protein and mRNA expression of Nrf2,SLC7A11,and GPX4(all P<0.01),and renal pathological damage was severe.Compared with the model group,24h-UTP,BUN,SCr,GLU,CHOL,TG levels were significantly reduced in the valsartan group,equal-Yi group and high-Yi group(all P<0.01),serum MDA levels were significantly reduced(P<0.01),XBP1,HRD1 protein and mRNA expressions in renal tissues were significantly reduced(all P<0.01),Nrf2,SLC7A11,GPX4 protein and mRNA expression were significantly increased(all P<0.01),and renal pathology was improved.Conclusion Yiqi Yangyin Huoxue Formu

关 键 词：益气养阴活血方 糖尿病肾病 内质网应激 铁死亡 XBP1/HRD1信号通路 

分 类 号：R285.5[医药卫生—中药学]