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

Sang Youb Han, Yi Hwa Jee, Kum Hyun Han, Young Sun Kang, Hyoung Kyu Kim, Jee Young Han, Young Sik Kim, Dae-Ryong Cha

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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.

Original languageEnglish
Pages (from-to)2406-2416
Number of pages11
JournalNephrology Dialysis Transplantation
Issue number9
Publication statusPublished - 2006 Sept

Bibliographical note

Funding Information:
Acknowledgements. This work was supported by the Basic Research Program of the Korean Science & Engineering Foundation (grant # R01-2002-000-00139-0) and by the Brain Korea 21 Project during 2004.


  • Angiotensin II
  • Diabetic nephropathy
  • High glucose
  • Matrix metalloproteinase-2
  • Proximal tubule cell
  • Tissue inhibitor of matrix metalloproteinase-2

ASJC Scopus subject areas

  • Nephrology
  • Transplantation


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