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
N1 - 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.
PY - 2006/9
Y1 - 2006/9
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-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.
AB - 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.
KW - Angiotensin II
KW - Diabetic nephropathy
KW - High glucose
KW - Matrix metalloproteinase-2
KW - Proximal tubule cell
KW - Tissue inhibitor of matrix metalloproteinase-2
UR - http://www.scopus.com/inward/record.url?scp=33750121618&partnerID=8YFLogxK
U2 - 10.1093/ndt/gfl238
DO - 10.1093/ndt/gfl238
M3 - Article
C2 - 16728425
AN - SCOPUS:33750121618
SN - 0931-0509
VL - 21
SP - 2406
EP - 2416
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 9
ER -