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An imbalance between matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 contributes to the development of early diabetic nephropathy.
Nephrol Dial Transplant. 2006 Sep; 21(9):2406-16.ND

Abstract

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-beta1 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-beta1, 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-beta1, MMP-2, TIMP-2, and in collagen production, suggesting the role of the AT1 receptor. The addition of exogenous TGF-beta1 produced an effect similar to those of high glucose and Ang-II. Furthermore, the inhibition of TGF-beta1 protein prevented Ang-II-induced MMP-2 and TIMP-2 alterations, suggesting the involvement of a TGF-beta1 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-beta1-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.

Authors+Show Affiliations

Department of Internal Medicine, Korea University Ansan-Hospital, 516 Kojan-Dong, Ansan City, Kyungki-Do 425-020, Korea. cdragn@unitel.co.krNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16728425

Citation

Han, Sang Youb, et al. "An Imbalance Between Matrix Metalloproteinase-2 and Tissue Inhibitor of Matrix Metalloproteinase-2 Contributes to the Development of Early Diabetic Nephropathy." Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association, vol. 21, no. 9, 2006, pp. 2406-16.
Han SY, Jee YH, Han KH, et al. An imbalance between matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 contributes to the development of early diabetic nephropathy. Nephrol Dial Transplant. 2006;21(9):2406-16.
Han, S. Y., Jee, Y. H., Han, K. H., Kang, Y. S., Kim, H. K., Han, J. Y., Kim, Y. S., & Cha, D. R. (2006). An imbalance between matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 contributes to the development of early diabetic nephropathy. Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association, 21(9), 2406-16.
Han SY, et al. An Imbalance Between Matrix Metalloproteinase-2 and Tissue Inhibitor of Matrix Metalloproteinase-2 Contributes to the Development of Early Diabetic Nephropathy. Nephrol Dial Transplant. 2006;21(9):2406-16. PubMed PMID: 16728425.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An imbalance between matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 contributes to the development of early diabetic nephropathy. AU - Han,Sang Youb, AU - Jee,Yi Hwa, AU - Han,Kum Hyun, AU - Kang,Young Sun, AU - Kim,Hyoung Kyu, AU - Han,Jee Young, AU - Kim,Young Sik, AU - Cha,Dae Ryong, Y1 - 2006/05/25/ PY - 2006/5/27/pubmed PY - 2006/10/13/medline PY - 2006/5/27/entrez SP - 2406 EP - 16 JF - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association JO - Nephrol Dial Transplant VL - 21 IS - 9 N2 - 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-beta1 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-beta1, 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-beta1, MMP-2, TIMP-2, and in collagen production, suggesting the role of the AT1 receptor. The addition of exogenous TGF-beta1 produced an effect similar to those of high glucose and Ang-II. Furthermore, the inhibition of TGF-beta1 protein prevented Ang-II-induced MMP-2 and TIMP-2 alterations, suggesting the involvement of a TGF-beta1 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-beta1-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. SN - 0931-0509 UR - https://www.unboundmedicine.com/medline/citation/16728425/An_imbalance_between_matrix_metalloproteinase_2_and_tissue_inhibitor_of_matrix_metalloproteinase_2_contributes_to_the_development_of_early_diabetic_nephropathy_ L2 - https://academic.oup.com/ndt/article-lookup/doi/10.1093/ndt/gfl238 DB - PRIME DP - Unbound Medicine ER -