Klotho protects against chronic kidney disease-associated atherosclerotic plaque vulnerability in mice

Xianjin BI; Jiangxin YANG; Jiachuan XIONG; Ke YANG; Jinghong ZHAO

doi:10.16016/j.1000-5404.201911180

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Klotho protects against chronic kidney disease-associated atherosclerotic plaque vulnerability in mice

Basic Medicine | 更新时间：2026-01-09

- Klotho protects against chronic kidney disease-associated atherosclerotic plaque vulnerability in mice
- Journal of Third Military Medical University Vol. 42, Issue 5, Pages: 460-465(2020)
- 作者机构：
  
  400037 重庆，陆军军医大学(第三军医大学)第二附属医院肾内科，全军肾脏病中心，重庆市慢性肾脏病防治重点实验室
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81873605);the National Natural Science Foundation for Young Scholars of China(81700379)
- DOI：10.16016/j.1000-5404.201911180
  CLC： R341;R543.5;R692
- Received：21 November 2019，
  
  Revised：2019-12-27，
  
  Published：15 March 2020
- 稿件说明：
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Xianjin BI, Jiangxin YANG, Jiachuan XIONG, et al. Klotho protects against chronic kidney disease-associated atherosclerotic plaque vulnerability in mice[J]. Journal of Third Military Medical University, 2020, 42(5): 460-465.
DOI：

Xianjin BI, Jiangxin YANG, Jiachuan XIONG, et al. Klotho protects against chronic kidney disease-associated atherosclerotic plaque vulnerability in mice[J]. Journal of Third Military Medical University, 2020, 42(5): 460-465. DOI： 10.16016/j.1000-5404.201911180.

摘要

目的

探讨慢性肾脏病(chronic kidney disease，CKD)对动脉粥样硬化斑块稳定性的影响和Klotho蛋白在此病理过程中的作用。

方法

采用8周龄雄性Apoe

-/-

小鼠制备5/6肾毁损CKD动物模型，高脂饮食12周，并通过腹腔注射Klotho蛋白(0.01 mg/kg，每2天注射1次)进行治疗。实验分为假手术组(sham组)、CKD组和Klotho+CKD组，每组8只小鼠。对各组小鼠主动脉根部层面切片，行HE和α-SMA免疫荧光染色，观察CKD对动脉粥样硬化斑块大小和纤维帽厚度的影响。体外培养人血管平滑肌(vascular smooth muscle cells，VSMCs)细胞，实验分4组，分别使用CKD 5期患者血清(CKD组)或者健康人血清(对照组)单独及联合Klotho蛋白进行孵育，观察各组细胞ROS水平和衰老细胞所占比例。

结果

与sham组比较，CKD组动脉粥样硬化斑块面积显著增加[(3.53±0.34)×10

(2.21±0.21)×10

μm

，

0.01

]

，纤维帽明显变薄，腹腔注射Klotho蛋白后可以显著抑制以上病理变化(

0.01)。与对照组比较，CKD组半乳糖苷酶阳性VSMCs细胞比例明显增加(

0.01)，VSMCs细胞ROS水平显著增加(

0.01)，Klotho蛋白预孵育后能显著抑制CKD导致的半乳糖苷酶阳性VSMCs细胞增加(

0.01)和ROS水平增加(

0.01)。

结论

VSMCs细胞衰老是CKD导致动脉粥样硬化斑块不稳定性发生的重要原因，Klotho蛋白在此过程中发挥保护作用。

Abstract

Objective

To explore the effects of chronic kidney disease (CKD) on the instability of atherosclerotic plaques and investigate the role of Klotho in this pathological process.

Methods

A total of 24 ApoE

-/-

mice (8 weeks old) were randomly divided into sham group

CKD group and CKD+Klotho group (

=8 in each group). Mouse model of CKD was established by 5/6 nephrectomy in the corresponding mice. Then

these mice were fed with high-fat diet for 12 weeks

and Klotho was supplemented intraperitoneally at 0.01 mg/kg

every other day to the mice from the CKD+Klotho group. HE staining and α-SMA immunofluorescence staining were performed to evaluate the effects of CKD and Klotho on the atherosclerotic plaque size and fibrous cap thickness. Cultured human vascular smooth muscle cells (VSMCs) were treated with the serum from CKD stage 5 patients or health individuals

in presence of Klotho protein. β-Gal staining and DCFH-DA probe were conducted to detect the proportion of senescent VSMCs and production of reactive oxygen species (ROS).

Results

The CKD group had significantly enlarged atherosclerotic plaque size

and decreased fibrous cap thickness (8.43±1.74

21.21±2.27 μm

0.01) when compared with the sham group. Supplement of Klotho could reverse these effects (

0.01).

In vitro

experiment showed that there were larger proportion of galactosidase positive cells and higher ROS level in the VSMCs treated with the serum form CKD patients (

0.01). However

pre-incubation of Klotho could alleviate theses effects (

0.01).

Conclusion

Senescence of VSMCs is an important reason for instability of atherosclerotic plaques caused by CKD

and Klotho plays a protective role in the process.

关键词

Keywords

references

RUIZ-HURTADO G, SARAFIDIS P, FERNÁNDEZ-ALFONSO M S, et al . Global cardiovascular protection in chronic kidney disease[J ] . Nat Rev Cardiol, 2016, 13(10): 603-608. DOI:10.1038/nrcardio.2016.48.

WEBSTER A C, NAGLER E V, MORTON R L, et al . Chronic kidney disease[J ] . Lancet, 2017, 389(10075): 1238-1252. DOI:10.1016/s0140-6736(16)32064-5.

RAGGI P, GENEST J, GILES J T, et al . Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions[J ] . Atherosclerosis, 2018, 276: 98-108. DOI:10.1016/j.atherosclerosis.2018.07.014.

CHISTIAKOV D A, OREKHOV A N, BOBRYSHEV Y V. Vascular smooth muscle cell in atherosclerosis[J]. Acta Physiol (Oxf), 2015, 214(1): 33-50. DOI:10.1111/apha.12466.

WANG J L, URYGA A K, REINHOLD J, et al . Vascular smooth muscle cell senescence promotes atherosclerosis and features of plaque vulnerability[J ] . Circulation, 2015, 132(20): 1909-1919. DOI:10.1161/CIRCULATIONAHA.115.016457.

ROMAGNANI P, REMUZZI G, GLASSOCK R, et al . Chronic kidney disease[J ] . Nat Rev Dis Primers, 2017, 3: 17088. DOI:10.1038/nrdp.2017.88.

JHA V, GARCIA-GARCIA G, ISEKI K, et al . Chronic kidney disease: global dimension and perspectives[J ] . Lancet, 2013, 382(9888): 260-272. DOI:10.1016/S0140-6736(13)60687-X.

TSIRPANLIS G. Cellular senescence, cardiovascular risk, and CKD: a review of established and hypothetical interconnections[J]. Am J Kidney Dis, 2008, 51(1): 131-144. DOI:10.1053/j.ajkd.2007.07.035.

KURO-O M, MATSUMURA Y, AIZAWA H, et al . Mutation of the mouse klotho gene leads to a syndrome resembling ageing[J ] . Nature, 1997, 390(6655): 45-51. DOI:10.1038/36285.

XU Y C, SUN Z J. Molecular basis of klotho: from gene to function in aging[J]. Endocr Rev, 2015, 36(2): 174-193. DOI:10.1210/er.2013-1079.

YANG K, NIE L, HUANG Y J, et al . Amelioration of uremic toxin indoxyl sulfate-induced endothelial cell dysfunction by Klotho protein[J ] . Toxicol Lett, 2012, 215(2): 77-83. DOI:10.1016/j.toxlet.2012.10.004.

YANG K, WANG C, NIE L, et al . Klotho protects against indoxyl sulphate-induced myocardial hypertrophy[J ] . J Am Soc Nephrol, 2015, 26(10): 2434-2446. DOI:10.1681/ASN.2014060543.

YANG K, DU C H, WANG X M, et al . Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice[J ] . Blood, 2017, 129(19): 2667-2679. DOI:10.1182/blood-2016-10-744060.

YU J, DENG M Y, ZHAO J H, et al . Decreased expression of klotho gene in uremic atherosclerosis in apolipoprotein E-deficient mice[J ] . Biochem Biophys Res Commun, 2010, 391(1): 261-266. DOI:10.1016/j.bbrc.2009.11.046.

BRO S, BENTZON J F, FALK E, et al . Chronic renal failure accelerates atherogenesis in apolipoprotein E-deficient mice[J ] . J Am Soc Nephrol, 2003, 14(10): 2466-2474. DOI:10.1097/01.asn.0000088024.72216.2e.

CAI Q J, MUKKU V K, AHMAD M. Coronary artery disease in patients with chronic kidney disease: a clinical update[J]. Curr Cardiol Rev, 2013, 9(4): 331-339. DOI:10.2174/1573403x10666140214122234.

BOUZID M A, FILAIRE E, MCCALL A, et al . Radical oxygen species, exercise and aging: an update[J ] . Sports Med, 2015, 45(9): 1245-1261. DOI:10.1007/s40279-015-0348-1.

CHILDS B G, DURIK M, BAKER D J, et al . Cellular senescence in aging and age-related disease: from mechanisms to therapy[J ] . Nat Med, 2015, 21(12): 1424-1435. DOI:10.1038/nm.4000.

SALAZAR G. NADPH oxidases and mitochondria in vascular senescence[J]. Int J Mol Sci, 2018,19(5): E1327. DOI:10.3390/ijms19051327.

VENDROV A E, VENDROV K C, SMITH A, et al . NOX4 NADPH oxidase-dependent mitochondrial oxidative stress in aging-associated cardiovascular disease[J ] . Antioxid Redox Signal, 2015, 23(18): 1389-1409. DOI:10.1089/ars.2014.6221.

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