Aim. The objective of this study was to characterize coordinated molecular changes in the structure and composition of the walls of venous segments of arteriovenous (AV) fistulas evoked by overflow. Methods. Venous tissue samples were collected from 6 hemodialysis patients with AV fistulas exposed to overflow and from the normal cephalic veins of 4 other hemodialysis patients. Total RNA was extracted from the venous tissue samples, and gene expression between the 2 groups was compared using Whole Human Genome DNA microarray 44?K. Microarray data were analyzed by GeneSpring GX software and Ingenuity Pathway Analysis. Results. The cDNA microarray analysis identified 397 upregulated genes and 456 downregulated genes. Gene ontology analysis with GeneSpring GX software revealed that biological developmental processes and glycosaminoglycan binding were the most upregulated. In addition, most upregulation occurred extracellularly. In the pathway analysis, the TGF beta signaling pathway, cytokines and inflammatory response pathway, hypertrophy model, and the myometrial relaxation and contraction pathway were significantly upregulated compared with the control cephalic vein. Conclusion. Combining microarray results and pathway information available via the Internet provided biological insight into the structure and composition of the venous wall of overflow AV fistulas. 1. Introduction Arteriovenous (AV) fistulas are very useful for determining optimal blood flow for dialysis, but AV fistulas exposed to overflow are thought to increase cardiac output and cause high-output cardiac failure [1, 2]. Measurement of blood flow via an internal shunt was first developed by Krivitski et al., and the monitoring of blood flow via a shunt has since become widespread [3]. We use this technique to monitor the blood flow of AV fistulas at our hospital and correct overflow AV fistulas with surgery. It is thought that the outflow vein of overflow AV fistulas bears a heavy load: as the vein is exposed to increased arterial flow, the wall dilates, triggering a vascular remodeling process. However, the molecular mechanisms by which the outflow vein is remodeled into a mature fistula remain unclear. By investigating venous remodeling in overflow AV fistulas, candidate genes important to the remodeling process can be discovered and their functional significance investigated. Thus, the identification of relevant genes involved in this process should provide insight into AV fistula maturation. In this study, we performed a cDNA microarray analysis and compared segments of the venous
References
[1]
S. Ohira, H. Naito, I. Amano et al., “2005 Japanese Society for Dialysis Therapy guidelines for vascular access construction and repair for chronic hemodialysis,” Therapeutic Apheresis and Dialysis, vol. 10, no. 5, pp. 449–462, 2006.
[2]
C. Basile, C. Lomonte, L. Vernaglione, F. Casucci, M. Antonelli, and N. Losurdo, “The relationship between the flow of arteriovenous fistula and cardiac output in haemodialysis patients,” Nephrology Dialysis Transplantation, vol. 23, no. 1, pp. 282–287, 2008.
[3]
N. M. Krivitski, “Theory and validation of access flow measurement by dilution technique during hemodialysis,” Kidney International, vol. 48, no. 1, pp. 244–250, 1995.
[4]
T. Lee and P. Roy-Chaudhury, “Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis,” Advances in Chronic Kidney Disease, vol. 16, no. 5, pp. 329–338, 2009.
[5]
P. Roy-Chaudhury, Y. Wang, M. Krishnamoorthy et al., “Cellular phenotypes in human stenotic lesions from haemodialysis vascular access,” Nephrology Dialysis Transplantation, vol. 24, no. 9, pp. 2786–2791, 2009.
[6]
D. Abeles, S. Kwei, G. Stavrakis, Y. Zhang, E. T. Wang, and G. García-Carde?a, “Gene expression changes evoked in a venous segment exposed to arterial flow,” Journal of Vascular Surgery, vol. 44, no. 4, pp. 863–870, 2006.
[7]
K. B. Boyle, D. Hadaschik, S. Virtue et al., “The transcription factors Egr1 and Egr2 have opposing influences on adipocyte differentiation,” Cell Death and Differentiation, vol. 16, no. 5, pp. 782–789, 2009.
[8]
J. Kumbrink, K. H. Kirsch, and J. P. Johnson, “EGR1, EGR2, and EGR3 activate the expression of their coregulator NAB2 establishing a negative feedback loop in cells of neuroectodermal and epithelial origin,” Journal of Cellular Biochemistry, vol. 111, no. 1, pp. 207–217, 2010.
[9]
L. Marconcini, S. Marchio, L. Morbidelli et al., “c-fos-Induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 17, pp. 9671–9676, 1999.
[10]
V. Schettler, K. V?lker, E. G. Schulz, and E. Wieland, “Impact of lipid apheresis on Egr-1, c-Jun, c-Fos, and Hsp70 gene expression in white blood cells,” Therapeutic Apheresis and Dialysis, vol. 15, no. 1, pp. 105–112, 2011.
[11]
K. Maehara, K. Oh-Hashi, and K. I. Isobe, “Early growth-responsive-1-dependent manganese superoxide dismutase gene transcription mediated by platelet-derived growth factor,” The FASEB Journal, vol. 15, no. 11, pp. 2025–2026, 2001.
[12]
J. Wenk, P. Brenneisen, M. Wlaschek et al., “Stable overexpression of manganese superoxide dismutase in mitochondria identifies hydrogen peroxide as a major oxidant in the AP-1-mediated induction of matrix-degrading metalloprotease-1,” The Journal of Biological Chemistry, vol. 274, no. 36, pp. 25869–25876, 1999.
[13]
T. Kondo, F. R. Sharp, J. Honkaniemi, S. Mikawa, C. J. Epstein, and P. H. Chan, “DNA fragmentation and prolonged expression of c-fos, c-jun, and hsp70 in kainic acid-induced neuronal cell death in transgenic mice overexpressing human CuZn-superoxide dismutase,” Journal of Cerebral Blood Flow and Metabolism, vol. 17, no. 3, pp. 241–256, 1997.
[14]
R. Pecoits-Filho, B. Lindholm, and P. Stenvinkel, “The malnutrition, inflammation, and atherosclerosis (MIA) syndrome—the heart of the matter,” Nephrology Dialysis Transplantation, vol. 17, supplement 11, pp. 28–31, 2002.