Advanced glycation end products decrease mesangial cell MMP-7: A role in matrix accumulation in diabetic nephropathy?

Susan V. Mclennan, D. J. Kelly, M. Schache, Mark Waltham, V. Dy, R. G. Langham, D. K. Yue, Richard E Gilbert

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51 Citations (Scopus)

Abstract

Increased extracellular matrix material is a pathological hallmark of diabetic nephropathy. In addition to collagens, a variety of non-collagenous glycoproteins such as fibronectin also accumulate in the kidney of diabetics. The effect of diabetes on degradative pathways, in particular those involving non-collagenous proteins, are relatively unexplored. In this study, we determined the expression of the major matrix metalloproteinase (MMP) responsible for degrading the non-collagenous matrix glycoprotein fibronectin. Furthermore, the modulation of these MMPs by advanced glycation end products (AGE), a key factor in the diabetic milieu, was explored. Exposure of mesangial cells to AGEs led to a significant reduction in MMP-7, but not MMP-3 or -10. MMP-7 expression was normalized by both aminoguanidine, an inhibitor of glycation product formation, or by a neutralizing anti-transforming growth factor-β (TGF-β) antibody. In streptozotocin-induced diabetic rats, the diminution in MMP-7 expression and excessive fibronectin accumulation were attenuated by aminoguanidine. Humans with type 2 diabetes and nephropathy displayed similar alterations in MMP-7 to their rodent counterparts. Our findings suggest that diminished expression of the glycoprotein-degrading enzyme, MMP-7, may play a role in fibronectin accumulation in the diabetic kidney in response to AGEs and/or TGF-β.

Original languageEnglish
Pages (from-to)481-488
Number of pages8
JournalKidney International
Volume72
Issue number4
DOIs
Publication statusPublished - Aug 2007
Externally publishedYes

Keywords

  • Advanced glycation end product
  • Diabetic nephropathy
  • Extracellular matrix
  • Fibronectin
  • Mesangial cells

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