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: 293/5/E1280    most recent 00223.2007v1 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 ISI Web of Science 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 (8) Citing Articles via Google Scholar Google Scholar Articles by Xia, L. Articles by Whiteside, C. I. Search for Related Content PubMed PubMed Citation Articles by Xia, L. Articles by Whiteside, C. I.

Reactive oxygen species, PKC-₁, and PKC- mediate high-glucose-induced vascular endothelial growth factor expression in mesangial cells

¹University Health Network, ³Mt. Sinai Hospital and ²Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Submitted 10 April 2007 ; accepted in final form 4 August 2007

Vascular endothelial growth factor (VEGF) is implicated in the development of proteinuria in diabetic nephropathy. High ambient glucose present in diabetes stimulates VEGF expression in several cell types, but the molecular mechanisms are incompletely understood. Here primary cultured rat mesangial cells served as a model to investigate the signal transduction pathways involved in high-glucose-induced VEGF expression. Exposure to high glucose (25 mM) significantly increased VEGF mRNA evaluated by real-time PCR by 3 h, VEGF cellular protein content assessed by immunoblotting or immunofluorescence within 24 h, and VEGF secretion by 24 h. High-glucose-induced VEGF expression was blocked by an antioxidant, Tempol, and antisense oligonucleotides directed against p22^phox, a NADPH oxidase subunit. Inhibition of protein kinase C (PKC)-₁ with the specific pharmacological inhibitor LY-333531 or inhibition of PKC- with a cell permeable specific pseudosubstrate peptide also prevented enhanced VEGF expression in high glucose. Enhanced VEGF secretion in high glucose was prevented by Tempol, PKC-₁, or PKC- inhibition. In normal glucose (5.6 mM), overexpression of p22^phox or constitutively active PKC- enhanced VEGF expression. Hypoxia inducible factor-1 protein was significantly increased in high glucose only by 24 h, suggesting a possible contribution to high-glucose-stimulated VEGF expression at later time points. Thus reactive oxygen species generated by NADPH oxidase, and both PKC-₁ and -, play important roles in high-glucose-stimulated VEGF expression and secretion by mesangial cells.

NADPH oxidase; vascular endothelial growth factor; p22^phox; protein kinase C-₁; protein kinase C-

This article has been cited by other articles:

				D. J. Kelly, A. J. Edgley, Y. Zhang, K. Thai, S. M. Tan, A. J. Cox, A. Advani, K. A. Connelly, C. I. Whiteside, and R. E. Gilbert Protein kinase C-{beta} inhibition attenuates the progression of nephropathy in non-diabetic kidney disease Nephrol. Dial. Transplant., June 1, 2009; 24(6): 1782 - 1790. [Abstract] [Full Text] [PDF]

				E. N. Lavrentyev and K. U. Malik High glucose-induced Nox1-derived superoxides downregulate PKC-{beta}II, which subsequently decreases ACE2 expression and ANG(1-7) formation in rat VSMCs Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H106 - H118. [Abstract] [Full Text] [PDF]

				L. Xia, H. Wang, S. Munk, J. Kwan, H. J. Goldberg, I. G. Fantus, and C. I. Whiteside High glucose activates PKC-{zeta} and NADPH oxidase through autocrine TGF-{beta}1 signaling in mesangial cells Am J Physiol Renal Physiol, December 1, 2008; 295(6): F1705 - F1714. [Abstract] [Full Text] [PDF]