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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