丹酚酸B基于Nrf2-Gpx4通路介导的铁死亡途径改善单侧输尿管梗阻大鼠肾脏间质纤维化

孙源博; 宋嫣然; 王诗琪; 孙丽欣; 李桂芹

doi:10.16016/j.2097-0927.202110189

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丹酚酸B基于Nrf2-Gpx4通路介导的铁死亡途径改善单侧输尿管梗阻大鼠肾脏间质纤维化

基础医学 | 更新时间：2026-01-09

- 丹酚酸B基于Nrf2-Gpx4通路介导的铁死亡途径改善单侧输尿管梗阻大鼠肾脏间质纤维化
- Salvianolic acid B attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction via Nrf2-Gpx4 pathway-mediated ferroptosis
- 陆军军医大学学报 2022年44卷第10期页码：1018-1024
- 作者机构：
  
  1.157000 黑龙江牡丹江，牡丹江医学院附属红旗医院肾脏内科
  2.157000 黑龙江牡丹江，牡丹江医学院附属红旗医院血液透析室
- 作者简介：
  
  [李桂芹，E-mail：liguiqin427@163.com LI Guiqin, E-mail: liguiqin427@163.com
- 基金信息：
  
  黑龙江省青年创新人才培养计划项目(UNPYSCT-2018120);黑龙江省省属高等学校基本科研业务费科研项目(2019-KYYWFMY-0047);“红旗科研基金”科技项目(2018HQ-05)
- DOI：10.16016/j.2097-0927.202110189
  中图分类号： R285.5;R692;R693.2
- 收稿：2021-10-29，
  
  修回：2022-01-27，
  
  纸质出版：2022-05-30
- 稿件说明：
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孙源博, 宋嫣然, 王诗琪, 等. 丹酚酸B基于Nrf2-Gpx4通路介导的铁死亡途径改善单侧输尿管梗阻大鼠肾脏间质纤维化[J]. 陆军军医大学学报, 2022,44(10):1018-1024.

Yuanbo SUN, Yanran SONG, Shiqi WANG, et al. Salvianolic acid B attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction via Nrf2-Gpx4 pathway-mediated ferroptosis[J]. Journal of Army Medical University, 2022, 44(10): 1018-1024.
孙源博, 宋嫣然, 王诗琪, 等. 丹酚酸B基于Nrf2-Gpx4通路介导的铁死亡途径改善单侧输尿管梗阻大鼠肾脏间质纤维化[J]. 陆军军医大学学报, 2022,44(10):1018-1024. DOI： 10.16016/j.2097-0927.202110189.

Yuanbo SUN, Yanran SONG, Shiqi WANG, et al. Salvianolic acid B attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction via Nrf2-Gpx4 pathway-mediated ferroptosis[J]. Journal of Army Medical University, 2022, 44(10): 1018-1024. DOI： 10.16016/j.2097-0927.202110189.

摘要

目的

基于核因子E2相关因子2(nuclear factor erythroid 2-related factor 2，Nrf2)-谷胱甘肽过氧化物酶4(glutathione peroxidase 4，Gpx4)通路介导的铁死亡途径，探究丹酚酸B对单侧输尿管梗阻(unilateral ureteral obstruction，UUO)大鼠肾脏间质纤维化(renal interstitial fibrosis，RIF)的改善作用。

方法

采用随机数字表法将40只大鼠分为假手术组、模型组、丹酚酸B组、丹酚酸B+Nrf2抑制剂组，每组10只。除假手术组外，其余各组建立UUO模型，假手术组除不结扎、剪断输尿管外，其余操作相同。丹酚酸B组灌胃100 mg·kg

-1

·d

-1

丹酚酸B，丹酚酸B+Nrf2抑制剂组在丹酚酸B组基础上腹腔注射Nrf2抑制剂ML385 30 mg·kg

-1

·d

-1

，假手术组、模型组灌胃等体积无菌生理盐水，连续9 d。HE染色和Masson染色检测肾组织形态和纤维化情况；试剂盒检测肾脏组织中Fe

、丙二醛(maleicdialdehyde，MDA)含量及超氧化物歧化酶(superoxide dismutase，SOD)活性；实时荧光定量PCR(quantitative real-time PCR，RT-qPCR)和蛋白质免疫印迹检测肾脏组织中Ⅰ型胶原(Collagen-Ⅰ，CoL-Ⅰ

)、Ⅲ型胶原(Collagen-Ⅲ，CoL-Ⅲ)、Nrf2、Gpx4的mRNA和蛋白水平。

结果

与假手术组相比，模型组肾脏组织中Fe

、MDA含量，CoL-Ⅰ、CoL-Ⅲ的mRNA和蛋白水平升高(

0.05)，血清中SOD活性降低(

0.05)，肾脏组织中Nrf2、Gpx4的mRNA和蛋白水平降低(

0.05)；与模型组相比，丹酚酸B组肾脏组织中Fe

、MDA含量，CoL-Ⅰ、CoL-Ⅲ的mRNA和蛋白水平降低(

0.05)，血清中SOD活性，肾脏组织中Nrf2、Gpx4的mRNA和蛋白水平升高(

0.05)；与丹酚酸B组相比，丹酚酸B+Nrf2抑制剂组肾脏组织中Fe

、MDA含量，CoL-Ⅰ、CoL-Ⅲ的mRNA和蛋白水平升高(

0.05)，血清中SOD活性，肾脏组织中Nrf2、Gpx4的mRNA和蛋白水平降低(

0.05)。

结论

丹酚酸B能够激活Nrf2-Gpx4通路进而抑制铁死亡实现对UUO大鼠RIF的缓解。

Abstract

Objective

To determine the improving effect of salvianolic acid B on renal interstitial fibrosis (RIF) of rats with unilateral ureteral obstruction (UUO) based on ferroptosis mediated by nuclear factor erythroid 2-related factor 2 (Nrf2)-glutathione peroxidase 4 (Gpx4) pathway.

Methods

A total of 40 rats were divided into sham operation group

model group

salvianolic acid B group

and salvianolic acid B+Nrf2 inhibitor group

with 10 rats in each group. UUO model was established in the latter 3 groups

and those of the sham operation group received the same operation except for not ligating and cutting the ureter. Salvianolic acid B of 100 mg·kg

-1

·d

-1

and Nrf2 inhibitor ML385 of 30 mg·kg

-1

·d

-1

were intragastrically administered to the corresponding groups

and sterile normal saline of equal volume was given to the sham operation group and model group

for 9 consecutive days. Hematoxylin-eosin (HE) staining and Masson staining were used to detect the morphology and fibrosis in renal tissues. The contents of Fe

maleicdialdehyde (MDA) and activity of superoxide dismutase (SOD) in renal tissues were detected with corresponding kits. Quantitative real-time P

CR (RT-qPCR) and Western blotting were used to detect the mRNA and protein levels of Collagen-Ⅰ (CoL-Ⅰ)

Collagen-Ⅲ (CoL-Ⅲ)

Nrf2

and Gpx4 in the renal tissues.

Results

Compared with the sham operation group

the contents of Fe

and MDA and the mRNA and protein levels of CoL-Ⅰ and CoL-Ⅲ in the renal tissues were increased (

0.05)

and the serum SOD activity and the mRNA and protein levels of Nrf2 were decreased (

0.05) in the model group. While the contents of Fe

and MDA and the mRNA and protein levels of CoL-Ⅰ and CoL-Ⅲ were decreased (

0.05)

and the SOD activity and the levels of Nrf2 and Gpx4 were increased (

0.05) in the salvianolic acid B group than the model group. The treatment of salvianolic acid B+Nrf2 inhibitor increased the contents of Fe

and MDA and the mRNA and protein levels of CoL-Ⅰ and CoL-Ⅲ (

0.05)

and reduced the SOD activity and the levels of Nrf2 and Gpx4 (

0.05) when compared with the salvianolic acid B group.

Conclusion

Salvianolic acid B activates the Nrf2-Gpx4 pathway and then inhibits ferroptosis to relieve RIF in UUO rats.

关键词

Keywords

references

VARGHESE R, MAJUMDAR A. Current therapies in nephrotic syndrome: HDAC inhibitors, an emerging therapy for kidney diseases[J]. Curr Res Biotechnol, 2021, 3: 182-194. DOI: 10.1016/j.crbiot.2021.05.007.

路萍, 许化溪. ILC2s与糖尿病肾病血液透析患者机体内"代谢综合征"状态的关系研究[J]. 重庆医科大学学报, 2020, 45(3): 378-387. DOI: 10.13406/j.cnki.cyxb.002115.

LU P, XU H X. Relationship between ILC2s and metabolic syndrome in hemodialysis patients with diabetic nephropathy[J]. J Chongqing Med Univ, 2020, 45(3): 378-387. DOI: 10.13406/j.cnki.cyxb.002115.

POSSELT J, HARBECK B, RAHVAR A H, et al . Improved cognitive function after kidney transplantation compared to hemodialysis[J ] . Ther Apher Dial, 2021, 25(6): 931-938. DOI: 10.1111/1744-9987.13625.

LI L, ZHANG Y Y, MA J J, et al . Salvia miltiorrhiza injection ameliorates renal damage induced by lead exposure in mice[J ] . Sci World J, 2014, 2014: 572697. DOI: 10.1155/2014/572697.

ZHANG Y, ZHANG Y Y, XIE Y, et al . Multitargeted inhibition of hepatic fibrosis in chronic iron-overloaded mice by Salvia miltiorrhiza[J ] . J Ethnopharmacol, 2013, 148(2): 671-681. DOI: 10.1016/j.jep.2013.05.028.

ZHANG Y Y, XUE Y C, ZHENG B, et al . Salvia miltiorrhiza (SM) injection ameliorates iron overloa d-associated cardiac dysfunction by regulating the expression of DMT1, TfR1, and FP 1 in rats[J ] . Evid Based Complement Alternat Med, 2021, 2021: 6864723. DOI: 10.1155/2021/6864723..

李均, 付旭, 姚兰, 等. 丹酚酸B, C分子药对配伍对UUO大鼠肾间质纤维化的保护作用及机制[J]. 中国实验方剂学杂志, 2015, 21(20): 113-117. DOI: 10.13422/j.cnki.syfjx.2015200113.

LI J, FU X, YAO L, et al . Protection and mechanism of compatibility of salvianolic acid B, C on renal interstitial fibrosis in UUO rats[J ] . Chin J Exp Tradit Med Formulae, 2015, 21(20): 113-117. DOI: 10.13422/j.cnki.syfjx.2015200113.

ZHAO G R, ZHANG H M, YE T X, et al . Characterization of the radical scavenging and antioxidant activities of danshensu and salvianolic acid B[J ] . Food Chem Toxicol, 2008, 46(1): 73-81. DOI: 10.1016/j.fct.2007.06.034.

CHEN S N, LIU Y Q, ZHU L, et al . Chaotrope-controlled fabrication of ferritin-salvianolic acid B—epigallocatechin gallate three-layer nanoparticle by the flexibility of ferritin channels[J ] . J Agric Food Chem, 2021, 69(41): 12314-12322. DOI: 10.1021/acs.jafc.1c01997.

HE Y, LU R R, WU J B, et al . Salvianolic acid B attenuates epithelial-mesenchymal transition in renal fibrosis rats through activating Sirt1-mediated autoph agy[J ] . Biomedecine Pharmacother, 2020, 128: 110241. DOI: 10.1016/j.biopha.2020.110241.

韩瑞祎. 铁死亡及其在肾脏疾病中的研究进展[J]. 国际儿科学杂志, 2021, 48(3): 173-177. DOI: 10.3760/cma.j.issn.1673-4408.2021.03.007.

HAN R Y. Progress of ferroptosis and its role in kidney disease[J]. Int J Pediatr, 2021, 48(3): 173-177. DOI: 10.3760/cma.j.issn.1673-4408.2021.03.007.

XIAO Z, LIU W, MU Y P, et al . Pharmacological effects of salvianolic acid B against oxidative damage[J ] . Front Pharmacol, 2020, 11: 572373. DOI: 10.3389/fphar.2020.572373.

LIU L R, LIU F, GUAN Y J, et al . Critical roles of SMYD2 lysine methyltransferase in mediating renal fibroblast activation and kidney fibrosis[J ] . FASEB J, 2021, 35(7): e21715. DOI: 10.1096/fj.202000554RRR.

韩宇鹏, 孟庆云, 杨舒贺, 等. 尿毒清颗粒对单侧输尿管梗阻大鼠肾间质纤维化及肾功能和转化生长因子-β1表达的影响[J]. 中国老年学杂志, 2020, 40(22): 4839-4841. DOI: 10.3969/j.issn.1005-9202.2020.22.041.

HAN Y P, MENG Q Y, YANG S H, et al . Effects of Niaoduqing granules on renal interstitial fibrosis and renal function and expression of transforming growth factor-β1 in rats with unilateral ureteral obstruction[J ] . Chin J Gerontol, 2020, 40(22): 4839-4841. DOI: 10.3969/j.issn.100 5-9202.2020.22.041.

李红莲, 周桔, 林华, 等. 丹酚酸B通过抗炎、抗氧化和促进自噬减轻慢性肾小球肾炎的肾功能损伤[J]. 中药药理与临床, 2019, 35(5): 34-38. DOI: 10.13412/j.cnki.zyyl.2019.05.008.

LI H L, ZHOU J, LIN H, et al . Salvianolic acid B attenuates renal dysfunction in chronic glomerulonephritis through anti-inflammatory, anti-oxidation and promoting autophagy[J ] . Pharmacol Clin Chin Mater Med, 2019, 35(5): 34-38. DOI: 10.13412/j.cnki.zyyl.2019.05.008.

凌林, 佟晶, 曾良. 芍药苷通过激活Nrf2/Keap1信号通路改善脓毒症急性肺损伤的研究[J]. 四川大学学报(医学版), 2020, 51(5): 664-669. DOI: 10.12182/20200960201.

LING L, TONG J, ZENG L. Paeoniflorin improves acute lung injury in Sepsis by activating Nrf2/Keap1 signaling pathway[J]. J Sichuan Univ Med Sci Ed, 2020, 51(5): 664-669. DOI: 10.12182/20200960201.

李荣荣, 马华, 田树杰, 等. 芪红通瘀饮对肾间质纤维化大鼠肾组织Wnt/β-catenin信号通路的影响[J]. 中华中医药杂志, 2020, 35(4): 1755-1759.

LI R R, MA H, TIAN S J, et al . Effects of Qihong Tongyu Decoction on Wnt/β-catenin signaling pathway in renal tissue of rats with renal interstitial fibrosis[J ] . China J Tradit Chin Med Pharm, 2020, 35(4): 1755-1759.

孙宁远, 朱雪林, 陈君. 丹参化学成分抗纤维化药理作用及机制研究进展[J]. 中国实验方剂学杂志, 2020, 26(22): 201-208. DOI: 10.13422/j.cnki.syfjx.20201870.

SUN N Y, ZHU X L, CHEN J. Research progress of anti-fibrosis pharmacological effect and mechanisms of chemical components in salviae miltiorrhizae Radix et rhizoma[J]. Chin J Exp Tradit Med Formulae, 2020, 26(22): 201-208. DOI: 10.13422/j.cnki.syfjx.20201870.

ZHONG Z Q, LI H Y, ZHONG H Z, et al . All-trans retinoic acid regulating angiopoietins-1 and alleviating extracellular matrix accumulation in interstitial fibrosis rats[J ] . Ren Fail, 2021, 43(1): 658-663. DOI: 10.1080/0886022X.2021.1910046.

DIXON S J, LEMBERG K M, LAMPRECHT M R, et al . Ferroptosis: an iron-dependent form of nonapoptotic cell death[J ] . Cell, 2012, 149(5): 1060-1072. DOI: 10.1016/j.cell.2012.03.042.

PANY Z, TANG P J, CAO J, et al . Lipid peroxidation aggravates anti-tuberculosis drug-induced liver injury: evidence of ferroptosis induction[J ] . Biochem Biophys Res Commun, 2020, 533(4): 1512-1518. DOI: 10.1016/j.bbrc.2020.09.140.

BAY1R H, ANTHONYMUTHU T S, TYURINA Y Y, et al . Achieving life through death: redox biology of lipid peroxidation in ferroptosis[J ] . Cell Chem Biol, 2020, 27(4): 387-408. DOI: 10.1016/j.chembiol.2020.03.014.

XIE Y, HOU W, SONG X, et al . Ferroptosis: process and function[J ] . Cell Death Differ, 2016, 23(3): 369-379. DOI: 10.1038/cdd.2015.158.

钟桂玲, 李文祥, 王贺, 等. 普罗布考经Nrf2/Gpx4途径抑制铁死亡保护H9C2心肌细胞[J]. 广西医科大学学报, 2021, 38(3): 462-467. DOI: 10.16190/j.cnki.45-1211/r.2021.03.007.

ZHONG G L, LI W X, WANG H, et al . Probucol inhibits ferroptosis via Nrf2/Gpx4 pathway to protect H9C2 cardiomyocytes[J ] . J Guangxi Med Univ, 2021, 38(3): 462-467. DOI: 10.16190/j.cnki.45-1211/r.2021.03.007..

FENG X M, WANG S, SUN Z C, et al . Ferroptosis enhanced diabetic renal tubular injury via HIF-1α/HO-1 pathway in db/db mice[J ] . Front Endocrinol (Lausanne), 2021, 12: 626390. DOI: 10.3389/fendo.2021.626390..

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