An imbalance between matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 contributes to the development of early diabetic nephropathy

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2006-09, Vol.21 (9), p.2406-2416
• Main Authors: Han, Sang Youb, Jee, Yi Hwa, Han, Kum Hyun, Kang, Young Sun, Kim, Hyoung Kyu, Han, Jee Young, Kim, Young Sik, Cha, Dae Ryong
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; angiotensin II; Angiotensin II - pharmacology; Animals; Associated diseases and complications; Biological and medical sciences; Blotting, Western; Cell Line; Collagen Type IV - drug effects; Collagen Type IV - genetics; Collagen Type IV - metabolism; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - enzymology; Diabetic Nephropathies - pathology; diabetic nephropathy; Emergency and intensive care: renal failure. Dialysis management; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Gene Expression; Glomerulonephritis; Glucose - pharmacology; high glucose; Humans; Immunohistochemistry; In Vitro Techniques; Intensive care medicine; Kidney Tubules, Proximal - enzymology; Kidney Tubules, Proximal - pathology; Male; Matrix Metalloproteinase 2 - drug effects; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; matrix metalloproteinase-2; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Polymerase Chain Reaction; proximal tubule cell; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; tissue inhibitor of matrix metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-2 - drug effects; Tissue Inhibitor of Metalloproteinase-2 - genetics; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta1
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfl238

Background. High glucose and angiotensin-II (Ang-II) levels are the known important mediators of diabetic nephropathy. However, the effects of these mediators on matrix metalloproteinase-2 (MMP-2) and on tissue inhibitor of metalloproteinase-2 (TIMP-2) in proximal tubule cells have yet to be fully examined within the context of early stage diabetic nephropathy. Methods. In this study, we attempted to characterize changes in MMP-2 and TIMP-2 in streptozotocin-induced diabetic rats. To further examine the molecular mechanisms involved, we evaluated the effects of high glucose (30 mM) or Ang-II on MMP-2, TIMP-2 and collagen synthesis in proximal tubule cells, and investigated whether MMP-2 and TIMP-2 are regulated via the TGF-β1 pathway. Results. In streptozotocin-induced diabetic rats, TIMP-2 mRNA and protein levels were significantly higher than in controls. Urinary protein excretion also showed a significant positive correlation with glomerular and tubular TIMP-2 protein expressions, and a negative correlation with MMP-2 expression. In cultured cells, both high glucose and Ang-II induced significant increases in TGF-β1, TIMP-2, and in collagen synthesis, and significant decreases in MMP-2 gene expression and activity, and thus disrupted the balance between MMP-2 and TIMP-2. Moreover, treatment with a selective angiotensin type 1 (AT1) receptor antagonist significantly inhibited Ang-II mediated changes in TGF-β1, MMP-2, TIMP-2, and in collagen production, suggesting the role of the AT1 receptor. The addition of exogenous TGF-β1 produced an effect similar to those of high glucose and Ang-II. Furthermore, the inhibition of TGF-β1 protein prevented Ang-II-induced MMP-2 and TIMP-2 alterations, suggesting the involvement of a TGF-β1 pathway. Conclusions. High glucose or Ang-II treatment induce alterations in MMP-2 and TIMP-2 balance, which favour TIMP-2 over-activity. Moreover, Ang-II-mediated changes in the productions of MMP-2 and TIMP-2 occur via AT1 receptors and a TGF-β1-dependent mechanism. These results suggest that an imbalance between the MMP-2 and TIMP-2, caused primarily by an increase in TIMP-2 activity, contributes to the pathogenesis of diabetic nephropathy.