MicroRNA-92a Mediates Endothelial Dysfunction in CKD : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Shang, Fenqing*,†,‡; Wang, Shen-Chih§,‖,¶; Hsu, Chien-Yi**,††,‡‡; Miao, Yifei§§; Martin, Marcy§; Yin, Yanjun*,†; Wu, Chih-Cheng‖‖,¶¶; Wang, Yun-Ting§§; Wu, Gaihong***; Chien, Shu§,†††; Huang, Hsien-Da‖; Tarng, Der-Cherng‡‡‡,§§§; Shiu, Yan-Ting‖‖‖; Cheung, Alfred K.‖‖‖,¶¶¶,****; Huang, Po-Hsun*,††; Chen, Zhen§§§; Shyy, John Y.-J.*,†,§

*Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China;

†Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education of China, Xi’an, China;

‡Division of Cardiology, The First Hospital of Xi’an, Xi’an, China;

§Department of Medicine, School of Medicine and

†††Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California;

‖Department of Biological Science and Technology, Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsin-Chu, Taiwan;

¶Department of Anesthesiology, Taipei Veterans General Hospital,

**Cardiovascular Research Center, and

‡‡‡Institutes of Physiology and Clinical Medicine, Genome Research and Infection and Immunity Centers, National Yang-Ming University, Taipei, Taiwan;

††Division of Cardiology, Department of Medicine and

§§§Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;

‡‡Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan;

§§Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, California;

‖‖Cardiovascular Center, National Taiwan University Hospital, Hsinchu Branch, Taipei, Taiwan;

¶¶Institute of Biomedical Engineering, National Tsing-Hua University, Hsinchu, Taiwan;

***Department of Nephrology, Xi’an GaoXin Hospital, Xi’an, China;

‖‖‖Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah, Salt Lake City, Utah;

¶¶¶Medical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah; and

****Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

F.S. and S.-C.W. contributed equally to this work.

Correspondence: Dr. Po-Hsun Huang, No. 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan, Dr. Zhen Chen, 1500 East Duarte Road, Duarte, CA 91010, or Dr. John Y.-J. Shyy, 76 Yanta West Road, Xi’an, China 710061. Email: [email protected], [email protected], or [email protected]

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.