2008 JASN IMPACT FACTOR 7.505	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2005090918v1 17/5/1405    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Katavetin, P. Articles by Nangaku, M. Search for Related Content PubMed PubMed Citation Articles by Katavetin, P. Articles by Nangaku, M.

High Glucose Blunts Vascular Endothelial Growth Factor Response to Hypoxia via the Oxidative Stress-Regulated Hypoxia-Inducible Factor/Hypoxia-Responsible Element Pathway

Pisut Katavetin^*, Toshio Miyata, Reiko Inagi^*, Tetsuhiro Tanaka^*, Ryoji Sassa, Julie R. Ingelfinger, Toshiro Fujita^* and Masaomi Nangaku^*

^* Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan; Molecular and Cellular Nephrology, Institute of Medical Sciences and Department of Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Okazaki Kita Clinic, Aichi, Japan; and Division of Pediatric Nephrology, Massachusetts General Hospital, Boston, Massachusetts

Address correspondence to: Dr. Masaomi Nangaku, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Phone: +81-3-3815-5411; Fax: +81-3-5800-8806; E-mail: mnangaku-tky{at}umin.ac.jp

Received for publication September 7, 2005. Accepted for publication March 4, 2006.

Vascular endothelial growth factor (VEGF) is an important survival factor for endothelial cells in hypoxic environments. High glucose regulates certain aspects of VEGF expression in various cell types, including proximal tubular cells. Thus, ambient glucose levels may modulate the progression of chronic kidney disease, especially diabetic nephropathy. Immortalized rat proximal tubular cells (IRPTC) were cultured for 24 h under hypoxic conditions (1% O₂), with or without high d-glucose (25 mM), or with or without high l-glucose (25 mM). Controls included culture in normoxic conditions and normal d-glucose (5.5 mM). VEGF mRNA expression was assessed by real-time quantitative PCR, and VEGF protein in the supernatant was assessed by ELISA. Hypoxia increased VEGF expression. This response was significantly blunted by high d-glucose (1.98 ± 0.11- versus 2.65 ± 0.27-fold increase for VEGF mRNA expression, 252.8 ± 14.7 versus 324.0 ± 11.5 pg/10⁵ cells for VEGF protein; P < 0.05 both) but not by high l-glucose. It is interesting that hydrogen peroxide also blunted this response, whereas -tocopherol restored the VEGF response to hypoxia in the presence of high d-glucose. For determination of involvement of the hypoxia-inducible factor (HIF)/hypoxia-responsible element (HRE) pathway, IRPTC that were stably transfected with HRE-luciferase were cultured under the previous conditions. High d-glucose also reduced luciferase activity under hypoxia, whereas -tocopherol restored activity. In vivo experiments using streptozotocin-induced diabetic rats confirmed that hyperglycemia blunted HIF-HRE pathway activation. Insulin treatment restored activation of the HIF-HRE pathway in streptozotocin-induced diabetic rats. In conclusion, high glucose blunts VEGF response to hypoxia in IRPTC. This effect is mediated by the oxidative stress-regulated HIF-HRE pathway.

This article has been cited by other articles:

				K. Takeda, T. Ichiki, E. Narabayashi, K. Inanaga, R. Miyazaki, T. Hashimoto, H. Matsuura, J. Ikeda, T. Miyata, and K. Sunagawa Inhibition of Prolyl Hydroxylase Domain-Containing Protein Suppressed Lipopolysaccharide-Induced TNF-{alpha} Expression Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 2132 - 2137. [Abstract] [Full Text] [PDF]

				L. Nordquist, R. Brown, A. Fasching, P. Persson, and F. Palm Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption Am J Physiol Renal Physiol, November 1, 2009; 297(5): F1265 - F1272. [Abstract] [Full Text] [PDF]

				J.-X. Chen and A. Stinnett Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1{alpha} (HIF-1{alpha})-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1{alpha} Expression, and Normalizes Immature Vasculature in db/db Mice Diabetes, December 1, 2008; 57(12): 3335 - 3343. [Abstract] [Full Text] [PDF]

				J. Ye, Z. Gao, J. Yin, and Q. He Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice Am J Physiol Endocrinol Metab, October 1, 2007; 293(4): E1118 - E1128. [Abstract] [Full Text] [PDF]

				M. T. Lindenmeyer, M. Kretzler, A. Boucherot, S. Berra, Y. Yasuda, A. Henger, F. Eichinger, S. Gaiser, H. Schmid, M. P. Rastaldi, et al. Interstitial Vascular Rarefaction and Reduced VEGF-A Expression in Human Diabetic Nephropathy J. Am. Soc. Nephrol., June 1, 2007; 18(6): 1765 - 1776. [Abstract] [Full Text] [PDF]

				M. Nangaku The Heat Is On: An Expanding Role for Hypoxia-Inducible Factors in Kidney Transplantation J. Am. Soc. Nephrol., January 1, 2007; 18(1): 13 - 15. [Full Text] [PDF]

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673