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

• Published in: Endocrinology (Philadelphia) Vol. 145; no. 12; pp. 5646 - 5655
• Main Authors: McLennan, S. V, Wang, X. Y, Moreno, V, Yue, D. K, Twigg, S. M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-12-2004; Oxford University Press
• Subjects: Animals; Antibodies; Antibodies - pharmacology; Biological and medical sciences; Cells, Cultured; Connective tissue; Connective Tissue Growth Factor; Connective tissues; Degradation; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme inhibitors; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Extracellular Matrix - metabolism; Fundamental and applied biological sciences. Psychology; Gelatinase A; Glomerular Mesangium - cytology; Glomerular Mesangium - metabolism; Glomerulus; Glucose; Glucose - pharmacology; Growth factors; Humans; Immediate-Early Proteins - metabolism; Immediate-Early Proteins - pharmacology; In vivo methods and tests; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Medical sciences; Mesangial cells; Metalloendopeptidases - metabolism; Metalloproteinase; mRNA; Nephropathy; Neutralizing; Rats; Rats, Inbred WF; Tissue inhibitor of metalloproteinase 1; Tissue inhibitor of metalloproteinase 2; Tissue inhibitor of metalloproteinase 3; Tissue Inhibitor of Metalloproteinase-1 - immunology; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Vertebrates: endocrinology; Endocrinopathy; Peptidases; Connective tissue; Enzyme; Diabetes mellitus; Tissue factor; Hydrolases; Metalloendopeptidases; Glucose; Growth factor
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2004-0436

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-β 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-β 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.