This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted 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 Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McLennan, S. V. Articles by Twigg, S. M. Search for Related Content PubMed PubMed Citation Articles by McLennan, S. V. Articles by Twigg, S. M.

Connective Tissue Growth Factor Mediates High Glucose Effects on Matrix Degradation through Tissue Inhibitor of Matrix Metalloproteinase Type 1: Implications for Diabetic Nephropathy

Department of Endocrinology, Royal Prince Alfred Hospital (S.V.M., V.M., D.K.Y., S.M.T.), and Discipline of Medicine (S.V.M., X.Y.W., D.K.Y., S.M.T.), University of Sydney, Sydney, New South Wales 2006, Australia

Address all correspondence and requests for reprints to: Dr. S. McLennan, Department of Medicine, University of Sydney, Sydney, New South Wales 2006, Australia. E-mail: sue{at}med.usyd.edu.au.

High glucose concentration inhibits matrix degradation and affects the activities of the enzymes responsible, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Connective tissue growth factor (CTGF) expression is increased in diabetic nephropathy and is a downstream mediator of TGF-ß actions. However, whether CTGF regulates matrix degradation and the mechanism of effect in diabetes has not been reported. Human mesangial cells were cultured in media containing 5 or 25 mM glucose and, in some experiments, with recombinant human (rh)CTGF (0–1000 ng/ml) and/or appropriate neutralizing antibodies. Matrix degradation was inhibited by rhCTGF in a dose-dependent manner, and the decrease in matrix degradation caused by high glucose and by TGF-ß was significantly attenuated by addition of CTGF-neutralizing antibody (by 40.2 and 69.1%, respectively). Similar to 25 mM glucose, addition of rhCTGF increased MMP-2, TIMP-1, and TIMP-3 mRNA by 2.5-, 2.1-, and 1.6-fold, respectively (P < 0.05) but had no effect on membrane-type (MT)1-MMP or TIMP-2. Addition of TIMP-1 antibody to conditioned medium abolished the decrease in degradation caused by rhCTGF and partially prevented (by 79%) the glucose-induced inhibition of matrix degradation. In vivo studies of glomeruli from diabetic and control rats showed that intensive insulin treatment prevented the increase in expression of CTGF and TIMP-1 and attenuated the decreased matrix degradation seen in diabetes. In summary, CTGF inhibits matrix degradation by increasing TIMP-1 expression, and by this action it contributes to the inhibition of matrix breakdown by high glucose, implying that CTGF has a role in the reduced matrix degradation observed in diabetic nephropathy.

This article has been cited by other articles:

				X. Wang, S. V. McLennan, T. J. Allen, T. Tsoutsman, C. Semsarian, and S. M. Twigg Adverse effects of high glucose and free fatty acid on cardiomyocytes are mediated by connective tissue growth factor Am J Physiol Cell Physiol, December 1, 2009; 297(6): C1490 - C1500. [Abstract] [Full Text] [PDF]

				C.-H. Cheng, T. Kikuchi, Y.-H. Chen, N. G. A.-A.-A. Sabbagha, Y.-C. Lee, H.-J. Pan, C. Chang, and Y.-T. Chen Mutations in the SLC2A10 gene cause arterial abnormalities in mice Cardiovasc Res, February 1, 2009; 81(2): 381 - 388. [Abstract] [Full Text] [PDF]

				G. P. Bertenshaw, P. Yip, P. Seshaiah, J. Zhao, T.-H. Chen, W. S. Wiggins, J. P. Mapes, and B. C. Mansfield Multianalyte Profiling of Serum Antigens and Autoimmune and Infectious Disease Molecules to Identify Biomarkers Dysregulated in Epithelial Ovarian Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2008; 17(10): 2872 - 2881. [Abstract] [Full Text] [PDF]

				J. T. M. Tan, S. V. McLennan, W. W. Song, L. W.-Y. Lo, J. G. Bonner, P. F. Williams, and S. M. Twigg Connective tissue growth factor inhibits adipocyte differentiation Am J Physiol Cell Physiol, September 1, 2008; 295(3): C740 - C751. [Abstract] [Full Text] [PDF]

				E. J. Kuiper, R. van Zijderveld, P. Roestenberg, K. M. Lyons, R. Goldschmeding, I. Klaassen, C. J.F. Van Noorden, and R. O. Schlingemann Connective Tissue Growth Factor Is Necessary for Retinal Capillary Basal Lamina Thickening in Diabetic Mice J. Histochem. Cytochem., August 1, 2008; 56(8): 785 - 792. [Abstract] [Full Text] [PDF]

				L. A. Maile, B. E. Capps, E. C. Miller, L. B. Allen, U. Veluvolu, A. W. Aday, and D. R. Clemmons Glucose Regulation of Integrin-Associated Protein Cleavage Controls the Response of Vascular Smooth Muscle Cells to Insulin-Like Growth Factor-I Mol. Endocrinol., May 1, 2008; 22(5): 1226 - 1237. [Abstract] [Full Text] [PDF]

				M. Guha, Z.-G. Xu, D. Tung, L. Lanting, and R. Natarajan Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes FASEB J, October 1, 2007; 21(12): 3355 - 3368. [Abstract] [Full Text] [PDF]

				E. J. Kuiper, J. M. Hughes, R. J. Van Geest, I. M. C. Vogels, R. Goldschmeding, C. J. F. Van Noorden, R. O. Schlingemann, and I. Klaassen Effect of VEGF-A on Expression of Profibrotic Growth Factor and Extracellular Matrix Genes in the Retina Invest. Ophthalmol. Vis. Sci., September 1, 2007; 48(9): 4267 - 4276. [Abstract] [Full Text] [PDF]

				S. Krag, J. R. Nyengaard, and L. Wogensen Combined effects of moderately elevated blood glucose and locally produced TGF-{beta}1 on glomerular morphology and renal collagen production Nephrol. Dial. Transplant., September 1, 2007; 22(9): 2485 - 2496. [Abstract] [Full Text] [PDF]

				M. Bajaj, R. Medina-Navarro, S. Suraamornkul, C. Meyer, R. A. DeFronzo, and L. J. Mandarino Paradoxical Changes in Muscle Gene Expression in Insulin-Resistant Subjects After Sustained Reduction in Plasma Free Fatty Acid Concentration Diabetes, March 1, 2007; 56(3): 743 - 752. [Abstract] [Full Text] [PDF]

				W. C. Burns, S. M. Twigg, J. M. Forbes, J. Pete, C. Tikellis, V. Thallas-Bonke, M. C. Thomas, M. E. Cooper, and P. Kantharidis Connective Tissue Growth Factor Plays an Important Role in Advanced Glycation End Product-Induced Tubular Epithelial-to-Mesenchymal Transition: Implications for Diabetic Renal Disease J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2484 - 2494. [Abstract] [Full Text] [PDF]

				W. E. Rodriguez, N. Tyagi, I. G. Joshua, J. C. Passmore, J. T. Fleming, J. C. Falcone, and S. C. Tyagi Pioglitazone mitigates renal glomerular vascular changes in high-fat, high-calorie-induced type 2 diabetes mellitus Am J Physiol Renal Physiol, September 1, 2006; 291(3): F694 - F701. [Abstract] [Full Text] [PDF]

				V. Portik-Dobos, A. K. Harris, W. Song, J. Hutchinson, M. H. Johnson, J. D. Imig, D. M. Pollock, and A. Ergul Endothelin antagonism prevents early EGFR transactivation but not increased matrix metalloproteinase activity in diabetes Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2006; 290(2): R435 - R441. [Abstract] [Full Text] [PDF]

				L. Xia, H. Wang, H. J. Goldberg, S. Munk, I. G. Fantus, and C. I. Whiteside Mesangial cell NADPH oxidase upregulation in high glucose is protein kinase C dependent and required for collagen IV expression Am J Physiol Renal Physiol, February 1, 2006; 290(2): F345 - F356. [Abstract] [Full Text] [PDF]

				P. R. A. Johnson, J. K. Burgess, Q. Ge, M. Poniris, S. Boustany, S. M. Twigg, and J. L. Black Connective Tissue Growth Factor Induces Extracellular Matrix in Asthmatic Airway Smooth Muscle Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 32 - 41. [Abstract] [Full Text] [PDF]

				J. K. Burgess, Q. Ge, M. H. Poniris, S. Boustany, S. M. Twigg, J. L. Black, and P. R. A. Johnson Connective tissue growth factor and vascular endothelial growth factor from airway smooth muscle interact with the extracellular matrix Am J Physiol Lung Cell Mol Physiol, January 1, 2006; 290(1): L153 - L161. [Abstract] [Full Text] [PDF]

				R Kane, L Stevenson, C Godson, A W Stitt, and C O'Brien Gremlin gene expression in bovine retinal pericytes exposed to elevated glucose Br J Ophthalmol, December 1, 2005; 89(12): 1638 - 1642. [Abstract] [Full Text] [PDF]

				Z. He, K. J. Way, E. Arikawa, E. Chou, D. M. Opland, A. Clermont, K. Isshiki, R. C. W. Ma, J. A. Scott, F. J. Schoen, et al. Differential Regulation of Angiotensin II-induced Expression of Connective Tissue Growth Factor by Protein Kinase C Isoforms in the Myocardium J. Biol. Chem., April 22, 2005; 280(16): 15719 - 15726. [Abstract] [Full Text] [PDF]