硫氧还蛋白相互作用蛋白通过诱导氧化应激促进肾脏纤维化的发生

何其睿; 李杨; 邓文珍; 刘东方

doi:10.16016/j.1000-5404.201805196

您当前的位置：

首页 >

文章列表页 >

硫氧还蛋白相互作用蛋白通过诱导氧化应激促进肾脏纤维化的发生

基础医学 | 更新时间：2026-01-09

- 硫氧还蛋白相互作用蛋白通过诱导氧化应激促进肾脏纤维化的发生
- Thioredoxin-interacting protein promotes renal fibrosis in mice by inducing oxidative stress
- 第三军医大学学报 2018年40卷第22期页码：2061-2067
- 作者机构：
  
  400010 重庆, 重庆医科大学附属第二医院内分泌科
- 作者简介：
  
  [ 刘东方，E-mail: ldf023023@qq.com LIU Dongfang, E-mail: ldf023023@qq.com
- 基金信息：
  
  国家自然科学基金面上项目(81370467);重庆市卫生和计划生育委员会科研项目(2016ZDXM011);重庆市社会事业与民生保障科技创新专项(CSTC2017shmsA130069)
- DOI：10.16016/j.1000-5404.201805196
  中图分类号： R341;R363.21;R692
- 收稿：2018-05-15，
  
  修回：2018-08-06，
  
  纸质出版：2018-11-30
- 稿件说明：
移动端阅览
何其睿, 李杨, 邓文珍, 等. 硫氧还蛋白相互作用蛋白通过诱导氧化应激促进肾脏纤维化的发生[J]. 第三军医大学学报, 2018,40(22):2061-2067.

Qirui HE, Yang LI, Wenzhen DENG, et al. Thioredoxin-interacting protein promotes renal fibrosis in mice by inducing oxidative stress[J]. Journal of Third Military Medical University, 2018, 40(22): 2061-2067.
何其睿, 李杨, 邓文珍, 等. 硫氧还蛋白相互作用蛋白通过诱导氧化应激促进肾脏纤维化的发生[J]. 第三军医大学学报, 2018,40(22):2061-2067. DOI： 10.16016/j.1000-5404.201805196.

Qirui HE, Yang LI, Wenzhen DENG, et al. Thioredoxin-interacting protein promotes renal fibrosis in mice by inducing oxidative stress[J]. Journal of Third Military Medical University, 2018, 40(22): 2061-2067. DOI： 10.16016/j.1000-5404.201805196.

摘要

目的

探讨硫氧还蛋白相互作用蛋白(thioredoxin interaction protein

TXNIP)对肾脏纤维化的作用。

方法

将12只SPF级C57BL/6J小鼠和12只TXNIP基因敲除鼠(TXNIP

-/-

)均按随机数字表法分为2组：正常对照组(normal control group

NC组)和高脂饮食组(high-fat diet group

HFD组)，喂养16周后取其肾组织，用HE、PAS及Masson染色方法观察肾脏组织病理变化及纤维化改变，采用免疫荧光法检测α-平滑肌肌动蛋白(α-SMA)在肾脏组织的表达水平，并通过Western blot检测肾脏组织中TXNIP、TGF-β1、α-SMA、p38 MAPK及p-p38 MAPK的表达情况。

结果

NC组与HFD组中TXNIP

-/-

小鼠的肾脏纤维化程度及p-p38 MAPK蛋白表达水平均明显低于C57BL/6J小鼠(

0.05)；而C57BL/6J小鼠HFD组与NC组相比，TXNIP在肾脏表达明显上调，且肾脏纤维化及p38磷酸化水平明显增加(

0.05)。

结论

硫氧还蛋白相互作用蛋白可能促进高脂诱导下肾脏纤维化，其作用机制可能与激活p38 MAPK信号通路有关。

Abstract

Objective

To investigate the role of thioredoxin-interacting protein (TXNIP) in high-fat diet-induced renal fibrosis.

Methods

Specific pathogen-free C57BL/6J mice and TXNIP knockout mice (TXNIP

-/-

) were both randomly divided into normal control group and high-fat diet group. After 16 weeks of feeding

the mice were sacrificed and the kidneys were dissected to observe the pathological changes and fibrotic changes using HE

PAS and Masson staining. The expression of α-smooth muscle actin (α-SMA) in the renal tissue was detected using immunofluorescence assay; Western blotting was used to detect the expression of TXNIP

α-SMA

transforming growth factor-β1 (TGF-β1)

p38 mitogen

-activated protein kinase (p38 MAPK) and its phosphorylation (p-p38 MAPK) in the renal tissue.

Results

TXNIP

-/-

mice fed on both normal and high-fat diet showed significantly lower expression levels of p-p38 MAPK and milder renal fibrosis than C57BL/6J mice (

0.05). Compared with the normal control mice

C57BL/6J mice fed on high-fat diet had significantly increased expression of TXNIP and p-p38 MAPK in the kidneys and more obvious renal fibrosis (

0.05).

Conclusion

TXNIP plays a role in promoting renal fibrosis in mice fed on high-fat diet

and its mechanism may involve the activation of p38 MAPK signaling pathway.

关键词

Keywords

references

ZHANG L, WANG F, WANG L, et al . Prevalence of chronic kidney disease in China: a cross-sectional survey[J ] . Lancet, 2012, 379(9818): 815-822. DOI: 10. 1016/S0140-6736(12)60033-6.

DUFFIELD J S. Cellular and molecular mechanisms in kidney fibrosis[J]. J Clin Invest, 2014, 124(6): 2299-2306. DOI: 10.1172/JCI72267.

ZHONG J, GUO D, CHEN C B, et al . Prevention of angiotensin Ⅱ-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2[J ] . Hypertension, 2011, 57(2): 314-322. DOI: 10.1161/HYPERTENSIONAHA.110.164244.

GRANDE M T, SÁNCHEZ-LAORDEN B, LÓPEZ-BLAU C, et al . Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease[J ] . Nat Med, 2015, 21(9): 989-997. DOI: 10.1038/nm.3901.

LV W, BOOZ G W, FAN F, et al . Oxidative stress and renal fibrosis: recent insights for the development of novel therapeutic strategies[J ] . Front Physiol, 2018, 9: 105. DOI: 10.3389/fphys.2018.00105.

RICHTER K, KONZACK A, PIHLAJANIEMI T, et al . Redox-fibrosis: impact of TGFβ1 on ROS generators, mediators and functional consequences[J ] . Redox Biol, 2015, 6: 344-352. DOI: 10.1016/j.redox.2015.08.015.

YOSHIHARA E, MASAKI S, MATSUO Y, et al . Thioredoxin/Txnip: redoxisome, as a redox switch for the pathogenesis of diseases[J ] . Front Immunol, 2014, 4: 514. DOI: 10.3389/fimmu.2013.00514.

HAMADA Y, FUKAGAWA M. A possible role of thioredoxin interacting protein in the pathogenesis of streptozotocin-induced diabetic nephropathy[J]. Kobe J Med Sci, 2007, 53(1/2): 53-61.

SHAH A, XIA L, MASSON E A, et al . Thioredoxin-inter-acting protein deficiency protects against diabetic nephropathy[J ] . J Am Soc Nephrol, 2015, 26(12): 2963-2977. DOI: 10.1681/ASN.2014050528.

TAN C Y, WEIER Q, ZHANG Y, et al . Thioredoxin-interacting protein: a potential therapeutic target for treatment of progressive fibrosis in diabetic nephropathy[J ] . Nephron, 2015, 129(2): 109-127. DOI: 10.1159/000368238.

WEI J, SHI Y, HOU Y, et al . Knockdown of thioredoxin-interacting protein ameliorates high glucose-induced epithelial to mesenchymal transition in renal tubular epithelial cells[J ] . Cell Signal, 2013, 25(12): 2788-2796. DOI: 10.1016/j.cellsig.2013.09.009.

PINHAL C S, LOPES A, TORRES D B, et al . Time-course morphological and functional disorders of the kidney induced by long-term high-fat diet intake in female rats[J ] . Nephrol Dial Transplant, 2013, 28(10): 2464-2476. DOI: 10.1093/ndt/gft304.

CAO J, SODHI K, PURI N, et al . High fat diet enhances cardiac abnormalities in SHR rats: protective role of heme-oxygenase-adiponectinaxis[J ] . Diabetol Metab Syndr, 2011, 3(1): 37. DOI: 10.1186/1758-5996-3-37.

孙阳, 赵艳红, 卢永新, 等.肾脏纤维化的发病机制及治疗进展[J].实用临床医药杂志, 2015, 19(9): 173-176. DOI: 10.7619/jcmp.201509059.

SUN Y, ZHAO Y H, LU Y X, et al . Pathogenesis and treatment progress of renal fibrosis[J ] . J Clin Med Pract, 2015, 19(9): 173-176. DOI: 10.7619/jcmp.201509059.jcmp.201509059.

CHENG X, ZHENG X, SONG Y, et al . Apocynin attenuates renal fibrosis via inhibition of NOXs-ROS-ERK-myo-fibroblast accumulation in UUO rats[J ] . Free Radic Res, 2016, 50(8): 840-852. DOI: 10. 1080/10715762.2016.1181757..

REN Y, DU C, SHI Y, et al . The Sirt1 activator, SRT1720, attenuates renal fibrosis by inhibiting CTGF and oxidative s tress[J ] . Int J Mol Med, 2017, 39(5): 1317-1324. DOI: 10. 3892/ijmm.2017.2931.

霍振霞, 王保兴. p38MAPK在氧化应激诱导肾间质纤维化中的研究进展[J].中华临床医师杂志(电子版), 2016, 10(7): 1029-1032. DOI: 10.3877/cma.j.issn.1674- 0785.2016.07.026.

HUO Z X, WANG B X. Research progress of p38MAPK in oxidative stress-induced renalinterstitial fibrosis[J]. Chin J Clinicians(Electr Ed), 2016, 10(7): 1029- 1032. DOI: 10.3877/cma.j.issn.1674-0785.2016.07.026.

QI F, CAI P, LIU X, et al . Adenovirus-mediated P311 inhibits TGF-β1-induced epithelial-mesenchymal transition in NRK-52E cells via TGF-β1-Smad-ILK pathway[J ] . Biosci Trends, 2015, 9(5): 299-306. DOI: 10.5582/bst. 2015.01129..

TANG F, HAO Y, ZHANG X, et al . Effect of echinacoside on kidney fibrosis by inhibition of TGF-β1/Smads signaling pathway in the db/db mice model of diabetic nephropathy[J ] . Drug Des Devel Ther, 2017, 11: 2813-2826. DOI: 10.2147/DDDT.S143805.

XU L, CUI W H, ZHOU W C, et al . Activation of Wnt/β-catenin signalling is required for TGF-β/Smad2/3 signalling during myofibroblas proliferation[J ] . J Cell Mol Med, 2017, 21(8): 1545-1554. DOI: 10.1111/jcmm.13085.

邓文珍, 李杨, 贾彦军, 等.过表达硫氧还蛋白相互作用蛋白(TXNIP)通过激活p38MAPK通路促进MIN6细胞凋亡[J].细胞与分子免疫学杂志, 2017, 33(10): 1323-1327. DOI: 10.13423/j.cnki.cjcmi.008448.

DENG W Z, LI Y, JIA Y J, et al . Over-expression of thioredoxin-interacting protein promotes apoptosis of MIN6 cells via activating p38MAPK pathway[J ] . Chin J Cell Mol Immunol, 2017, 33(10): 1323-1327. DOI: 10.13423/j.cnki.cjcmi.008448..

邓小芳.黄芪三七合剂通过影响p38 MAPK的表达改善CKD大鼠肾脏纤维化[J].检验医学与临床, 2016, 13(11): 1494-1496. DOI: 10.3969/j.issn.1672-9455.2016.11.015.

DENG X F. Huangqisanqi mixture improves kidney fibrosis in CKD rats by affecting the expression of p38 MAPK[J]. Lab Med Clin, 2016, 13(11): 1494-1496. DOI: 10.3969/j.issn.1672-9455.2016.11.015.

TSIANI E, LEKAS P, FANTUS I G, et al . High glucose-enhanced activation of mesangial cell p38 MAPK by ET-1, ANG Ⅱ, and platelet-derived growth factor[J ] . Am J Physiol Endocrinol Metab, 2002, 282(1): E161-E169. DOI: 10.1152/ajpendo.2002.282.1.E161.

LI X, LIU W, WANG Q, et al . Emodin suppresses cell proliferation and fibronectin expression via p38MAPK pathway in rat mesangial cells cultured under high glucose[J ] . Mol Cell Endocrinol, 2009, 307(1/2): 157-162. DOI: 10.1016/j.mce.2009.03.006..

NISHIDA M, OKUMURA Y, SATO H, et al . Delayed inhibition of p38 mitogen-activated protein kinase ameliorates renal fibrosis in obstructive nephropathy[J ] . Nephrol Dial Transplant, 2008, 23(8): 2520-2524. DOI: 10. 1093/ndt/gfn309.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

GSK3β促进TGF-β1诱导的肾小管上皮HK-2细胞纤维化