Published Online
on August 25, 2003

A more recent version of this article appeared on September 1, 2003

This Article Full Text (PDF) All Versions of this Article: 42/3/335    most recent 01.HYP.0000087839.72582.DDv1 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 Lindschau, C. Articles by Haller, H. Search for Related Content PubMed PubMed Citation Articles by Lindschau, C. Articles by Haller, H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB GLUCOSE

Submitted on December 3, 2002
Revised on December 31, 2002

Glucose-Induced TGF-1 and TGF- Receptor-1 Expression in Vascular Smooth Muscle Cells Is Mediated by Protein Kinase C-

Carsten Lindschau; Petra Quass; Jan Menne; Faikah Güler; Anette Fiebeler; Michael Leitges; Friedrich C. Luft; and Hermann Haller^*

From the Department of Nephrology, Medical School Hannover (C.L., P.Q., J.M., F.G., A.F., H.H.), Hannover; the Max-Planck Institute for Experimental Endocrinology (M.L.), Hannover; and Helios-Klinikum, Franz Volhard Clinic, and the Max Delbrück Center for Molecular Medicine (F.C.L.), Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany.

^* To whom correspondence should be addressed. E-mail: haller.hermann{at}mh-hannover.de.

Abstract--Sclerosis and increased matrix expression in diabetes are mediated by glucose-induced transforming growth factor (TGF)-1 expression. The intracellular effects of high glucose occur at least in part by way of protein kinase C (PKC). We previously described a role for PKC- in glucose-induced permeability. We now investigated the hypothesis that glucose-induced expression of TGF-1 and its receptors (TGF--R1 and -R2) are mediated by activation of this PKC isoform. TGF-1 and TGF--R expressions were determined in vascular smooth muscle cells (VSMCs) by immunocytochemistry and Western blotting. PKC isoforms were assessed by confocal microscopy. PKC isoforms were inhibited with antisense oligodeoxynucleotides. PKC- was upregulated by overexpression or microinjection. High glucose (20 mmol/L) increased VSMC TGF-1 and TGF--R1 expression but not TGF--R2 expression. PKC inhibitors and specific PKC- downregulation by antisense treatment prevented this effect, whereas antisense treatment against PKC-, -, and - had no influence. PKC- overexpression increased TGF-1 and TGF--R1 expression but not TGF--R2 expression. PKC- microinjection into individual VSMCs also increased TGF-1 and TGF--R immunofluorescence. Last, VSMCs from PKC--deficient mice did not respond to high glucose compared with VSMCs from wild-type mice. We propose that high glucose-induced TGF-1 and TGF--R1 expression is mediated by PKC-. Our findings suggest an autocrine feedback mechanism and a possible role for PKC- in diabetic vascular disease.

Key words: glucose • growth substances • protein kinases • diabetes • muscle, vascular, smooth • atherosclerosis

This article has been cited by other articles:

				C. E. Hills, N. Al-Rasheed, N. Al-Rasheed, G. B. Willars, and N. J. Brunskill C-peptide reverses TGF-{beta}1-induced changes in renal proximal tubular cells: implications for treatment of diabetic nephropathy Am J Physiol Renal Physiol, March 1, 2009; 296(3): F614 - F621. [Abstract] [Full Text] [PDF]

				G. Spinetti, N. Kraenkel, C. Emanueli, and P. Madeddu Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies Cardiovasc Res, May 1, 2008; 78(2): 265 - 273. [Abstract] [Full Text] [PDF]

				M. Meier, J. Menne, J.-K. Park, and H. Haller Nailing down PKC isoform specificity in diabetic nephropathy two's company, three's a crowd Nephrol. Dial. Transplant., September 1, 2007; 22(9): 2421 - 2425. [Full Text] [PDF]

				M. Meier, J. Menne, J.-K. Park, M. Holtz, F. Gueler, T. Kirsch, M. Schiffer, M. Mengel, C. Lindschau, M. Leitges, et al. Deletion of Protein Kinase C-{varepsilon} Signaling Pathway Induces Glomerulosclerosis and Tubulointerstitial Fibrosis In Vivo J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1190 - 1198. [Abstract] [Full Text] [PDF]

				E. Mikaelsson, A. H. Danesh-Manesh, A. Luppert, M. Jeddi-Tehrani, M.-R. Rezvany, R. A. Sharifian, R. Safaie, A. Roohi, A. Osterborg, F. Shokri, et al. Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell chronic lymphocytic leukemia and mantle cell lymphoma Blood, June 15, 2005; 105(12): 4828 - 4835. [Abstract] [Full Text] [PDF]

				C. Rask-Madsen and G. L. King Proatherosclerotic Mechanisms Involving Protein Kinase C in Diabetes and Insulin Resistance Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 487 - 496. [Abstract] [Full Text] [PDF]

				J. Menne, J.-K. Park, M. Boehne, M. Elger, C. Lindschau, T. Kirsch, M. Meier, F. Gueler, A. Fiebeler, F. H. Bahlmann, et al. Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-{alpha}--Deficient Diabetic Mice Diabetes, August 1, 2004; 53(8): 2101 - 2109. [Abstract] [Full Text] [PDF]