HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 287/4/F658    most recent 00040.2004v1 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 ISI Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Nakagawa, T. Articles by Johnson, R. J. Search for Related Content PubMed PubMed Citation Articles by Nakagawa, T. Articles by Johnson, R. J.

Differential regulation of VEGF by TGF- and hypoxia in rat proximal tubular cells

¹Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida 32610-0224; ²Division of Nephrology-Medicine, Baylor College of Medicine, Houston, Texas 77030; ³Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria 3050, Australia; ⁴Division of Nephrology, Ewha Women's University Hospital, Seoul 158-710, Republic of Korea; and ⁵Scios, Incorporated, Sunnyvale, California 94085

Submitted 5 February 2004 ; accepted in final form 1 June 2004

VEGF expression by proximal tubular epithelial cells may play a critical role in maintaining peritubular capillary endothelium in renal disease. Two major processes involved in renal injury include hypoxia (from vasoconstriction or vascular injury) and transforming growth factor (TGF)--dependent fibrosis, both of which are known to stimulate VEGF. Because the TGF-/Smad pathway is activated in hypoxia, we tested the hypothesis that the induction of VEGF in hypoxia could be partially dependent on TGF-. Rat proximal tubular (NRK52E) cells treated with TGF- under normoxic conditions secreted VEGF at 24 h, and this was significantly reduced by blocking Smad activation by overexpressing the inhibitory Smad7 or by blocking p38 and ERK1/2 MAP kinase activation or protein kinase C activation with specific inhibitors. With acute hypoxia, rat proximal tubular cells also express VEGF mRNA and protein as well as TGF-. However, the induction of VEGF occurs before synthesis of TGF- and is not blocked by either a TGF- antagonist, by Smad7 overexpression, or by blockage of ERK1/2, whereas induction is blocked by PKC inhibition or partially blocked by a p38 inhibitor. Finally, the addition of TGF- with hypoxia results in significantly more VEGF expression than either stimulation alone. Thus TGF- and hypoxia act via additive/synergistic but distinct pathways to stimulate VEGF in proximal tubular cells, a finding that may be important in understanding how VEGF is stimulated in renal disease.

Smad; protein kinase C; mitogen-activated protein kinase; renal; angiogenesis; vascular endothelial growth factor; transforming growth factor-

This article has been cited by other articles:

				O. Glushakova, T. Kosugi, C. Roncal, W. Mu, M. Heinig, P. Cirillo, L. G. Sanchez-Lozada, R. J. Johnson, and T. Nakagawa Fructose Induces the Inflammatory Molecule ICAM-1 in Endothelial Cells J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1712 - 1720. [Abstract] [Full Text] [PDF]

				D. P. Basile, K. Fredrich, B. Chelladurai, E. C. Leonard, and A. R. Parrish Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1, a novel VEGF inhibitor Am J Physiol Renal Physiol, April 1, 2008; 294(4): F928 - F936. [Abstract] [Full Text] [PDF]

				R. Grenda, E. Wuhl, M. Litwin, R. Janas, J. Sladowska, K. Arbeiter, U. Berg, A. Caldas-Afonso, M. Fischbach, O. Mehls, et al. Urinary excretion of endothelin-1 (ET-1), transforming growth factor- 1 (TGF- 1) and vascular endothelial growth factor (VEGF165) in paediatric chronic kidney diseases: results of the ESCAPE trial Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3487 - 3494. [Abstract] [Full Text] [PDF]

				T. Nakagawa, W. Sato, O. Glushakova, M. Heinig, T. Clarke, M. Campbell-Thompson, Y. Yuzawa, M. A. Atkinson, R. J. Johnson, and B. Croker Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy J. Am. Soc. Nephrol., February 1, 2007; 18(2): 539 - 550. [Abstract] [Full Text] [PDF]

				E. de Laplanche, K. Gouget, G. Cleris, F. Dragounoff, J. Demont, A. Morales, L. Bezin, C. Godinot, G. Perriere, D. Mouchiroud, et al. Physiological oxygenation status is required for fully differentiated phenotype in kidney cortex proximal tubules Am J Physiol Renal Physiol, October 1, 2006; 291(4): F750 - F760. [Abstract] [Full Text] [PDF]

				T. Nakagawa, W. Sato, Y. Y. Sautin, O. Glushakova, B. Croker, M. A. Atkinson, C. C. Tisher, and R. J. Johnson Uncoupling of Vascular Endothelial Growth Factor with Nitric Oxide as a Mechanism for Diabetic Vasculopathy J. Am. Soc. Nephrol., March 1, 2006; 17(3): 736 - 745. [Abstract] [Full Text] [PDF]