干预血栓调节蛋白表达对糖尿病肾病肾损伤的影响

汪伟; 李怡; 吴松; 陈瑾; 王艳梅; 唐韵; 李贵森; 丁涵露

doi:10.16016/j.1000-5404.202007105

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干预血栓调节蛋白表达对糖尿病肾病肾损伤的影响

基础医学 | 更新时间：2026-01-09

- 干预血栓调节蛋白表达对糖尿病肾病肾损伤的影响
- Effect of modulating thrombomodulin expression on renal injury in rats with diabetic nephropathy
- 第三军医大学学报 2021年43卷第2期页码：156-162
- 作者机构：
  
  610072 成都，四川省人民医院肾内科，电子科技大学医学院四川省肾脏疾病临床研究中心
- 作者简介：
  
  [ 丁涵露, E-mail: dhanlu@163.com DING Hanlu, E-mail: dhanlu@163.com
- 基金信息：
  
  国家自然科学基金面上项目(81170680);四川省科技厅应用基础项目(2018JY0332);四川省人民医院2014年青年基金资助项目(3030503851)
- DOI：10.16016/j.1000-5404.202007105
  中图分类号： R692.9; TQ937
- 收稿：2020-07-12，
  
  修回：2020-09-07，
  
  纸质出版：2021-01-30
- 稿件说明：
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汪伟, 李怡, 吴松, 等. 干预血栓调节蛋白表达对糖尿病肾病肾损伤的影响[J]. 第三军医大学学报, 2021,43(2):156-162.

Wei WANG, Yi LI, Song WU, et al. Effect of modulating thrombomodulin expression on renal injury in rats with diabetic nephropathy[J]. Journal of Third Military Medical University, 2021, 43(2): 156-162.
汪伟, 李怡, 吴松, 等. 干预血栓调节蛋白表达对糖尿病肾病肾损伤的影响[J]. 第三军医大学学报, 2021,43(2):156-162. DOI： 10.16016/j.1000-5404.202007105.

Wei WANG, Yi LI, Song WU, et al. Effect of modulating thrombomodulin expression on renal injury in rats with diabetic nephropathy[J]. Journal of Third Military Medical University, 2021, 43(2): 156-162. DOI： 10.16016/j.1000-5404.202007105.

摘要

目的

探讨干预血栓调节蛋白(thrombomodulin，TM)表达对糖尿病肾病(diabetic nephropathy，DN)肾损伤的影响及可能机制。

方法

① 利用免疫组化检测25例DN患者肾组织以及6例正常肾组织中肝X受体-α(liver X receptor-α，LXR-α)、TM、凝血因子XⅢ- A(FXⅢ-A)和CD163表达；②在明确LXR-α激动剂T0901317上调db/db小鼠TM表达及TM干扰RNA(Ad-TM shRNA)下调TM表达作用后，将12周龄雄性db/db小鼠分为4组(

=6):DN生理盐水组、Ad-ctrl+DN组、T0901317+DN组、Ad-TM shRNA+DN组，C57BL6野生小鼠作为正常对照组。上述5组给药4周后，Western blot、免疫组化观察干预TM表达对肾组织TM、LXR-α、FXⅢ-A、CD163表达的影响，ELISA检测血炎症介质(TNF-α、IL-6)以及尿微量白蛋白的变化。

结果

DN患者肾组织TM、LXR-α表达量较对照组下降，且与肾小球滤过率正相关(

0.05)；而FXⅢ-A和CD163表达较对照组升高，且与肾小球滤过率负相关(

0.05)。动物实验显示:DN生理盐水组与野生小鼠对照组相比、Ad-TM shRNA组与DN对照组相比，均表现为尿微量白蛋白和血TNF-α、IL-6水平上升、肾组织TM和LXR-α表达减少、FXⅢ-A和CD163表达增加(

0.05)，而T0901317+DN组较DN对照组，上述指标改善。

结论

表达上调的TM可能通过抑制肾组织FXⅢ-A、CD163表达以及下调血炎症介质水平而改善db/db小鼠尿蛋白水平。

Abstract

Objective

To investigate the effect of modulating thrombomodulin (TM) expression on renal injury in a rat model of diabetic nephropathy (DN) and explore the possible mechanism.

Methods

We examined the expression of liver X receptor-α (LXR-α)

coagulation factor XⅢ-A (FXⅢ-A) and CD163 in 25 renal biopsy samples from patients with DN and in 6 normal renal tissue specimens using immunohistochemistry. Twenty-four 12-week-old male db/db mice with DN were randomly assigned into 4 equal groups and treated daily with intragastric administration of normal saline or LXR-α agonist T0901317

or with intravenous injection of an adenoviral vector carrying TM shRNA or the control adenoviral vector for 7 consecutive days; 6 wild-type C57BL6 mice with intragastric saline treatment served as the normal control group. Four weeks after the treatment

the expression of TM

LXR-α

FXⅢ-A and CD163 in the renal tissues of the mice were detected using Western blotting

the levels of tumor necrosis factor-α (TNF-α) and interleukine-6 (IL-6) were detected by ELISA

and the urinary microalbumin level was determined.

Results

The renal expression levels of TM and LXR-α were decreased (

0.05) and those of FXⅢ-A and CD163 were increased significantly (

0.05) in the kidney tissues of DN patients compared with normal kidney tissues. In db/db mouse model of DN

the expression levels of TM and LXR-α were positively correlated while those of FXⅢ-A and CD163 were negatively correlated with glomerular filtration rate (

0.05). Compared with the wild-type mice

the mouse model of DN showed significantly increased urinary microalbumin levels and serum levels of TNF-α and IL-6

lowered renal expressions of TM and LXR-α

and increased renal expression of FXⅢ-A and CD163; these changes were further exacerbated in the mice treated with Ad-TM shRNA (

0.05) but significantly improved in the mouse models treated with T0901317.

Conclusion

Upregulating TM expression can reduce urinary microalbumin level in db/db mouse model of DN by inhibiting the renal expression of FXⅢ-A and CD163 and downregulating blood levels of inflammatory mediators.

关键词

Keywords

references

ANDERS H J, HUBER T B, ISERMANN B, et al . CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease[J ] . Nat Rev Nephrol, 2018, 14(6): 361-377. DOI:10.1038/s41581-018-0001-y.

LOGHMANI H, CONWAY E M. Exploring traditional and nontraditional roles for thrombomodulin[J]. Blood, 2018, 132(2): 148-158. DOI:10.1182/blood-2017-12-768994.

FIUZA C, BUSTIN M, TALWAR S, et al . Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells[J ] . Blood, 2003, 101(7): 2652-2660. DOI:10.1182/blood-2002-05-1300.

DROŻDŻ D, ŁĄTKA M, DROŻDŻ T, et al . Thrombomodulin as a new marker of endothelial dysfunction in chronic kidney disease in children[J ] . Oxid Med Cell Longev, 2018, 2018: 1619293. DOI:10.1155/2018/1619293.

PHILIPPOU H, RANCE J, MYLES T, et al . Roles of low specificity and cofactor interaction sites on thrombin during factor XⅢ activation. Competition for cofactor sites on thrombin determines its fate[J ] . J Biol Chem, 2003, 278(34): 32020-32026. DOI:10.1074/jbc.m305364200.

TÖRÖCSIK D, BÁRDOS H, NAGY L, et al . Identification of factor XⅢ-A as a marker of alternative macrophage activation[J ] . Cell Mol Life Sci, 2005, 62(18): 2132-2139. DOI:10.1007/s00018-005-5242-9.

MYNENI V D, MOUSA A S, KAARTINEN M T. Factor XⅢ-A transglutaminase deficient mice show signs of metabolically healthy obesity on high fat diet[J]. Sci Rep, 2016, 6: 35574. DOI:10.1038/srep35574.

PALOMER X, GONZÁLEZ-CLEMENTE J M, BLANCO-VACA F, et al . Role of vitamin D in the pathogenesis of type 2 diabetes mellitus[J ] . Diabetes Obes Metab, 2008, 10(3): 185-197. DOI:10.1111/j.1463-1326.2007.00710.x.

DING H, LI Y, FENG Y, et al . LXR agonist T0901317 upregulates thrombomodulin expression in glomerular endothelial cells by inhibition of nuclear factor-κB[J ] . Mol M ed Rep, 2016, 13(6): 4888-4896. DOI:10.3892/mmr.2016.5138.

吴松, 李怡, 陈惠宇, 等.肝X受体激动剂对db、db鼠肾脏肝X受体表达及其活性的影响[J].实用医院临床杂志, 2018, 15(2): 1-3.

WU S, LI Y, CHEN H Y, et al . The effect of liver X receptor agonists on expressions and activity of liver X receptors in the kidney of db/db mice[J ] . Pract J Clin Med, 2018, 15(2): 1-3.

吴松, 杜亚琴, 张萍, 等. T0901317激活肝X受体α改善db/db小鼠肾损伤[J].第三军医大学学报, 2020, 42(1):75-80. DOI: 10.16016 /j.1000-5404.201907232.

WU S, DU Y Q, ZHANG P, et al . T0901317 improves renal injury in db /db mice by activating liver X receptor α[J ] . J Third Mil Med Univ, 2020, 42(1):75-80. DOI: 10.16016 /j.1000-5404.201907232.

PALLER M S, HOIDAL J R, FERRIS T F. Oxygen free radicals in ischemic acute renal failure in the rat[J]. J Clin Invest, 1984, 74(4): 1156-1164. DOI:10.1172/jci111524.

ISERMANN B, VINNIKOV I A, MADHUSUDHAN T, et al . Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis[J ] . Nat Med, 2007, 13(11): 1349-1358. DOI:10.1038/nm1667.

GUITERAS R, SOLA A, FLAQUER M, et al . Exploring macrophage cell therapy on diabetic kidney disease[J ] . J Cell Mol Med, 2019, 23(2): 841-851. DOI:10.1111/jcmm.13983.

TESCH G H. Role of macrophages in complications of type 2 diabetes[J]. Clin Exp Pharmacol Physiol, 2007, 34(10): 1016-1019. DOI:10.1111/j.1440-1681.2007.04729.x.

TÖRÖCSIK D, BÁRDOS H, HATALYÁK Z, et al . Detection of factor XⅢ-A is a valuable tool for distinguishing dendritic cells and tissue macrophages in granuloma annulare and necrobiosis lipoidica[J ] . J Eur Acad Dermatol Venereol, 2014, 28(8): 1087-1096. DOI:10.1111/jdv.12290.

DICKNEITE G, HERWALD H, KORTE W, et al . Coagulation factor XⅢ: a multifunctional transglutaminase with clinical potential in a range of conditions[J ] . Thromb Haemost, 2015, 113(4): 686-697. DOI:10.1160/th14-07-0625.

DARDIK R, LOSCALZO J, ESKARAEV R, et al . Molecular mechanisms underlying the proangiogenic effect of factor XⅢ[J ] . Arterioscler Thromb Vasc Biol, 2005, 25(3): 526-532. DOI:10.1161/01.atv.0000154137.21230.80.

ZAETS S B, XU D Z, LU Q, et al . Recombinant factor XⅢ mitigates hemorrhagic shock-induced organ dysfunction[J ] . J Surg Res, 2011, 166(2): e135-e142. DOI:10.1016/j.jss.2010.12.001.

LOOF T G, MÖRGELIN M, JOHANSSON L, et al . Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense[J ] . Blood, 2011, 118(9): 2589-2598. DOI:10.1182/blood-2011-02-337568.

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