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J Am Soc Nephrol. 2017 Nov;28(11):3251-3261. doi: 10.1681/ASN.2016111215. Epub 2017 Jul 10.

MicroRNA-92a Mediates Endothelial Dysfunction in CKD.

Shang F1,2,3, Wang SC4,5,6, Hsu CY7,8,9, Miao Y10, Martin M4, Yin Y1,2, Wu CC11,12, Wang YT10, Wu G13, Chien S4,14, Huang HD5, Tarng DC15,16, Shiu YT17, Cheung AK17,18,19, Huang PH20,8, Chen Z21, Shyy JY20,2,4.

Author information

1
Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
2
Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China.
3
Division of Cardiology, The First Hospital of Xi'an, Xi'an, China.
4
Department of Medicine, School of Medicine and.
5
Department of Biological Science and Technology, Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsin-Chu, Taiwan.
6
Department of Anesthesiology, Taipei Veterans General Hospital.
7
Cardiovascular Research Center, and.
8
Division of Cardiology, Department of Medicine and.
9
Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
10
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, California.
11
Cardiovascular Center, National Taiwan University Hospital, Hsinchu Branch, Taipei, Taiwan.
12
Institute of Biomedical Engineering, National Tsing-Hua University, Hsinchu, Taiwan.
13
Department of Nephrology, Xi'an GaoXin Hospital, Xi'an, China.
14
Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California.
15
Institutes of Physiology and Clinical Medicine, Genome Research and Infection and Immunity Centers, National Yang-Ming University, Taipei, Taiwan.
16
Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
17
Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
18
Medical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah; and.
19
Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
20
Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China; huangbsvgh@gmail.com zhenchen@coh.org jshyy@ucsd.edu.
21
Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; huangbsvgh@gmail.com zhenchen@coh.org jshyy@ucsd.edu.

Abstract

CKD is an independent risk factor for cardiovascular disease (CVD). The accumulation of uremic toxins in CKD induces oxidative stress and endothelial dysfunction. MicroRNA-92a (miR-92a) is induced by oxidative stress in endothelial cells (ECs) and involved in angiogenesis and atherosclerosis. We investigated a role for oxidative stress-responsive miR-92a in CKD. Our study of patients at three clinical sites showed increased serum miR-92a level with decreased kidney function. In cultured ECs, human CKD serum or uremic toxins (such as indoxyl sulfate), compared with non-CKD serum, induced the levels of miR-92a and suppressed the expression of miR-92a targets, including key endothelial-protective molecules. The antioxidant N-acetylcysteine inhibited these vasculopathic properties. In rats, adenine-induced CKD associated with increased levels of miR-92a in aortas, serum, and CD144+ endothelial microparticles. Furthermore, CD144+ microparticles from human uremic serum contained more miR-92a than those from control serum. Additional analysis showed a positive correlation between serum levels of miR-92a and indoxyl sulfate in a cohort of patients with ESRD undergoing hemodialysis. Collectively, our findings suggest that the uremic toxins accumulated in CKD can upregulate miR-92a in ECs, which impairs EC function and predisposes patients to CVD.

KEYWORDS:

chronic kidney disease; endothelial cells; microRNA-92; oxidative stress

PMID:
28696247
PMCID:
PMC5661278
[Available on 2018-11-01]
DOI:
10.1681/ASN.2016111215
[Indexed for MEDLINE]

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