miR-126 and miR-223 as biomarkers of vascular damage in the course of Chronic Kidney Disease

Valérie Metzinger-Le Meuth, Ziad A Massy, Laurent Metzinger


Development of disease is often due to deregulation of gene expression. The gene program is controlled at the post-transcriptional level by the action of small non-coding RNAs known as microRNAs (miRNAs), short, single-stranded molecules that control mRNA stability or translational repression via base pairing with regions in the 3' untranslated region of their target mRNAs. Over the last decade, considerable progress has been made to elucidate the roles of miRNAs in vascular pathogenesis and develop the use of miRNAs as innovative biomarkers in diagnostics, and as groundbreaking drugs in pharmacological treatments. It has been recently shown that several miRNAs are implicated in the course of chronic kidney disease (CKD) and are associated with vessel damage, such as vascular calcifications and atherosclerosis. The inflammatory miR-223 is increased in vitro in vascular smooth muscle cells subjected to uremic toxins and is also increased in vivo in more advanced stages of CKD. The endothelial-specific miR-126 is involved in vascular remodeling in response to laminar shear stress in HUVEC cells. Finally, miR-126 levels have been found to be deregulated in murine and human serum in the course of experimental CKD and in human diabetic patients. In conclusion, these miRNAs could play a role in CKD vascular remodeling and may therefore represent useful targets to prevent or treat complications of CKD.

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R. Madonna, R. De Caterina, Potential roles of vessel wall heparan sulfate proteoglycans in atherosclerosis, Vascul Pharmacol 60 (2014) 49-51.

Z.A. Massy, T.B. Drueke, Vascular calcification, Curr Opin Nephrol Hypertens 22 (2013) 405-412.

D.P. Bartel, MicroRNAs: target recognition and regulatory functions, Cell 136 (2009) 215-233.

S. Vijayarathna, C.E. Oon, S.L. Jothy, Y. Chen, J.R. Kanwar, S. Sasidharan, MicroRNA pathways: an emerging role in identification of therapeutic strategies, Curr Gene Ther 14 (2014) 112-120.

H. Guo, N.T. Ingolia, J.S. Weissman, D.P. Bartel, Mammalian microRNAs predominantly act to decrease target mRNA levels, Nature 466 (2010) 835-840.

N.X. Chen, K. Kiattisunthorn, K.D. O'Neill, X. Chen, R.N. Moorthi, V.H. Gattone, 2nd, M.R. Allen, S.M. Moe, Decreased microRNA is involved in the vascular remodeling abnormalities in chronic kidney disease (CKD), PLoS One 8 (2013) e64558.

F. Taibi, V. Metzinger-Le Meuth, Z.A. Massy, L. Metzinger, miR-223: An inflammatory oncomiR enters the cardiovascular field, Biochim Biophys Acta 1842 (2014) 1001-1009.

F. Taibi, V. Metzinger-Le Meuth, E. M'Baya-Moutoula, M. Djelouat, L. Louvet, J.M. Bugnicourt, S. Poirot, A. Bengrine, J.M. Chillon, Z.A. Massy, L. Metzinger, Possible involvement of microRNAs in vascular damage in experimental chronic kidney disease, Biochim Biophys Acta 1842 (2014) 88-98.

A.Y. Rangrez, E. M'Baya-Moutoula, V. Metzinger-Le Meuth, L. Henaut, M.S. Djelouat, J. Benchitrit, Z.A. Massy, L. Metzinger, Inorganic phosphate accelerates the migration of vascular smooth muscle cells: evidence for the involvement of miR-223, PLoS One 7 (2012) e47807.

S.B. Pushpakumar, S. Kundu, U. Sen, Endothelial dysfunction: The link between homocysteine and hydrogen sulfide, Curr Med Chem. (2014) epub ahead of print.

T.A. Harris, M. Yamakuchi, M. Ferlito, J.T. Mendell, C.J. Lowenstein, MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1, Proc Natl Acad Sci U S A 105 (2008) 1516-1521.

S.A. Asgeirsdottir, C. van Solingen, N.F. Kurniati, P.J. Zwiers, P. Heeringa, M. van Meurs, S.C. Satchell, M.A. Saleem, P.W. Mathieson, B. Banas, J.A. Kamps, T.J. Rabelink, A.J. van Zonneveld, G. Molema, MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation, Am J Physiol Renal Physiol 302 (2012) F1630-1639.

A. Zernecke, K. Bidzhekov, H. Noels, E. Shagdarsuren, L. Gan, B. Denecke, M. Hristov, T. Koppel, M.N. Jahantigh, E. Lutgens, S. Wang, E.N. Olson, A. Schober, C. Weber, Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection, Sci Signal 2 (2009) ra81.

C. van Solingen, H.C. de Boer, R. Bijkerk, M. Monge, A.M. van Oeveren-Rietdijk, L. Seghers, M.R. de Vries, E.P. van der Veer, P.H. Quax, T.J. Rabelink, A.J. van Zonneveld, MicroRNA-126 modulates endothelial SDF-1 expression and mobilization of Sca-1(+)/Lin(-) progenitor cells in ischaemia, Cardiovasc Res 92 (2011) 449-455.

S. Wang, A.B. Aurora, B.A. Johnson, X. Qi, J. McAnally, J.A. Hill, J.A. Richardson, R. Bassel-Duby, E.N. Olson, The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis, Dev Cell 15 (2008) 261-271.

J. Zhou, Y.S. Li, P. Nguyen, K.C. Wang, A. Weiss, Y.C. Kuo, J.J. Chiu, J.Y. Shyy, S. Chien, Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126: role of shear stress, Circ Res 113 (2013) 40-51.

S. Kumar, C.W. Kim, R.D. Simmons, H. Jo, Role of Flow-Sensitive microRNAs in Endothelial Dysfunction and Atherosclerosis: Mechanosensitive Athero-miRs, Arterioscler Thromb Vasc Biol. (2014) epub ahead of print

A. Schober, M. Nazari-Jahantigh, Y. Wei, K. Bidzhekov, F. Gremse, J. Grommes, R.T. Megens, K. Heyll, H. Noels, M. Hristov, S. Wang, F. Kiessling, E.N. Olson, C. Weber, MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1, Nat Med 20 (2014) 368-376.

J.M. Chillon, A. Mozar, I. Six, J. Maizel, J.M. Bugnicourt, S. Kamel, M. Slama, M. Brazier, Z.A. Massy, Pathophysiological mechanisms and consequences of cardiovascular calcifications: role of uremic toxicity, Ann Pharm Fr 67 (2009) 234-240.

Z.A. Massy, R. Mentaverri, A. Mozar, M. Brazier, S. Kamel, The pathophysiology of vascular calcification: are osteoclast-like cells the missing link?, Diabetes Metab 34 Suppl 1 (2008) S16-20.

P.S. Mitchell, R.K. Parkin, E.M. Kroh, B.R. Fritz, S.K. Wyman, E.L. Pogosova-Agadjanyan, A. Peterson, J. Noteboom, K.C. O'Briant, A. Allen, D.W. Lin, N. Urban, C.W. Drescher, B.S. Knudsen, D.L. Stirewalt, R. Gentleman, R.L. Vessella, P.S. Nelson, D.B. Martin, M. Tewari, Circulating microRNAs as stable blood-based markers for cancer detection, Proc Natl Acad Sci U S A 105 (2008) 10513-10518.

M.P. Hunter, N. Ismail, X. Zhang, B.D. Aguda, E.J. Lee, L. Yu, T. Xiao, J. Schafer, M.L. Lee, T.D. Schmittgen, S.P. Nana-Sinkam, D. Jarjoura, C.B. Marsh, Detection of microRNA expression in human peripheral blood microvesicles, PLoS One 3 (2008) e3694.

P. Menendez, P. Villarejo, D. Padilla, J.M. Menendez, J.A. Montes, Diagnostic and prognostic significance of serum microRNAs in colorectal cancer, J Surg Oncol 107 (2013) 217-220.

T.C. Roberts, A.M. Coenen-Stass, M.J. Wood, Assessment of RT-qPCR normalization strategies for accurate quantification of extracellular microRNAs in murine serum, PLoS One 9 (2014) e89237.

A. Zampetaki, S. Kiechl, I. Drozdov, P. Willeit, U. Mayr, M. Prokopi, A. Mayr, S. Weger, F. Oberhollenzer, E. Bonora, A. Shah, J. Willeit, M. Mayr, Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes, Circ Res 107 (2010) 810-817.

F. Jansen, X. Yang, M. Hoelscher, A. Cattelan, T. Schmitz, S. Proebsting, D. Wenzel, S. Vosen, B.S. Franklin, B.K. Fleischmann, G. Nickenig, N. Werner, Endothelial microparticle-mediated transfer of MicroRNA-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles, Circulation 128 (2013) 2026-2038.

V. Cantaluppi, S. Gatti, D. Medica, F. Figliolini, S. Bruno, M.C. Deregibus, A. Sordi, L. Biancone, C. Tetta, G. Camussi, Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells, Kidney Int 82 (2012) 412-427.

S. Albinsson, Y. Suarez, A. Skoura, S. Offermanns, J.M. Miano, W.C. Sessa, MicroRNAs are necessary for vascular smooth muscle growth, differentiation, and function, Arterioscler Thromb Vasc Biol 30 (2010) 1118-1126.

M. Abedin, Y. Tintut, L.L. Demer, Vascular calcification: mechanisms and clinical ramifications, Arterioscler Thromb Vasc Biol 24 (2004) 1161-1170.

L. Shi, B. Fisslthaler, N. Zippel, T. Fromel, J. Hu, A. Elgheznawy, H. Heide, R. Popp, I. Fleming, MicroRNA-223 antagonizes angiogenesis by targeting beta1 integrin and preventing growth factor signaling in endothelial cells, Circ Res 113 (2013) 1320-1330.

V. Metzinger-Le Meuth, S. Andrianome, J.M. Chillon, A. Bengrine, Z.A. Massy, L. Metzinger, microRNAs are dysregulated in the cerebral microvasculature of CKD mice, Front Biosci (Elite Ed) 6 (2014) 80-88.

F. Tabet, K.C. Vickers, L.F. Cuesta Torres, C.B. Wiese, B.M. Shoucri, G. Lambert, C. Catherinet, L. Prado-Lourenco, M.G. Levin, S. Thacker, P. Sethupathy, P.J. Barter, A.T. Remaley, K.A. Rye, HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells, Nat Commun 5 (2014) 3292.

J.W. Dear, J.M. Street, M.A. Bailey, Urinary exosomes: a reservoir for biomarker discovery and potential mediators of intrarenal signalling, Proteomics 13 (2013) 1572-1580.

DOI: http://dx.doi.org/10.14800/rd.347


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