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) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, S. Articles by Murphy-Ullrich, J. E. Search for Related Content PubMed PubMed Citation Articles by Wang, S. Articles by Murphy-Ullrich, J. E. Social Bookmarking                What's this?

Expression of Constitutively Active cGMP-Dependent Protein Kinase Prevents Glucose Stimulation of Thrombospondin 1 Expression and TGF-ß Activity

¹ Department of Pathology, Division of Molecular and Cellular Pathology, Cell Adhesion and Matrix Research Center, University of Alabama at Birmingham, Birmingham, Alabama
² Department of Surgery, University of Alabama at Birmingham, Alabama
³ Department of Physiology, University of South Alabama, School of Medicine, Mobile, Alabama

Hyperglycemia is a crucial factor in the development of diabetic nephropathy. We previously showed that high glucose upregulates thrombospondin 1 (TSP1)-dependent transforming growth factor (TGF)-ß activation by altering cGMP-dependent protein kinase (PKG) activity as a result of decreased nitric oxide signaling. In the present study, we showed that high glucose concentrations significantly reduced endogenous PKG activity. To further examine the mechanisms by which PKG regulates TSP1 expression and TSP1-dependent TGF-ß activation, we generated stably transfected rat mesangial cells (RMCs) with inducible expression tetracycline-induced gene expression of the catalytic domain of PKG. After tetracycline induction, the catalytic domain of PKG is expressed as a cGMP-independent active kinase. Expression of the catalytic domain prevented high glucose-mediated increases in transcription of the TSP1 gene with no alteration in TSP1 mRNA stability. Glucose stimulation of TSP1 protein expression and TGF-ß bioactivity were also downregulated. TGF-ß-dependent fibronectin and type IV collagen expression under high glucose conditions were significantly reduced upon catalytic domain expression in transfected RMCs. These results show that constitutively active PKG inhibits the fibrogenic potential of high glucose through repression of TSP1-dependent TGF-ß bioactivity, suggesting that gene transfer of the catalytic domain of PKG might provide a new strategy for treatment of diabetic renal fibrosis.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				F. Peng, D. Wu, B. Gao, A. J. Ingram, B. Zhang, K. Chorneyko, R. McKenzie, and J. C. Krepinsky RhoA/Rho-Kinase Contribute to the Pathogenesis of Diabetic Renal Disease Diabetes, June 1, 2008; 57(6): 1683 - 1692. [Abstract] [Full Text] [PDF]

				C. Daniel, K. Schaub, K. Amann, J. Lawler, and C. Hugo Thrombospondin-1 Is an Endogenous Activator of TGF-{beta} in Experimental Diabetic Nephropathy In Vivo Diabetes, December 1, 2007; 56(12): 2982 - 2989. [Abstract] [Full Text] [PDF]

				K. R. Kaun, C. A. L. Riedl, M. Chakaborty-Chatterjee, A. T. Belay, S. J. Douglas, A. G. Gibbs, and M. B. Sokolowski Natural variation in food acquisition mediated via a Drosophila cGMP-dependent protein kinase J. Exp. Biol., October 15, 2007; 210(20): 3547 - 3558. [Abstract] [Full Text] [PDF]

				P. Raman, I. Krukovets, T. E. Marinic, P. Bornstein, and O. I. Stenina Glycosylation Mediates Up-regulation of a Potent Antiangiogenic and Proatherogenic Protein, Thrombospondin-1, by Glucose in Vascular Smooth Muscle Cells J. Biol. Chem., February 23, 2007; 282(8): 5704 - 5714. [Abstract] [Full Text] [PDF]

				M. Saura, C. Zaragoza, B. Herranz, M. Griera, L. Diez-Marques, D. Rodriguez-Puyol, and M. Rodriguez-Puyol Nitric Oxide Regulates Transforming Growth Factor-{beta} Signaling in Endothelial Cells Circ. Res., November 25, 2005; 97(11): 1115 - 1123. [Abstract] [Full Text] [PDF]

				J.-S. Huang, L.-Y. Chuang, J.-Y. Guh, C.-J. Chen, Y.-L. Yang, T.-A. Chiang, M.-Y. Hung, and T.-N. Liao Effect of Nitric Oxide-cGMP-Dependent Protein Kinase Activation on Advanced Glycation End-Product-Induced Proliferation in Renal Fibroblasts J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2318 - 2329. [Abstract] [Full Text] [PDF]

				Y. Ihara, S. Manabe, M. Kanda, H. Kawano, T. Nakayama, I. Sekine, T. Kondo, and Y. Ito Increased expression of protein C-mannosylation in the aortic vessels of diabetic Zucker rats Glycobiology, April 1, 2005; 15(4): 383 - 392. [Abstract] [Full Text] [PDF]

				S. Wang, J. Skorczewski, X. Feng, L. Mei, and J. E. Murphy-Ullrich Glucose Up-regulates Thrombospondin 1 Gene Transcription and Transforming Growth Factor-{beta} Activity through Antagonism of cGMP-dependent Protein Kinase Repression via Upstream Stimulatory Factor 2 J. Biol. Chem., August 13, 2004; 279(33): 34311 - 34322. [Abstract] [Full Text] [PDF]