Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy

Lab Invest. 2012 Aug;92(8):1149-60. doi: 10.1038/labinvest.2012.68. Epub 2012 May 21.


Renal fibrosis is a common finding in progressive renal diseases. Matrix metalloproteinases (MMPs) are involved in epithelial-to-mesenchymal transition (EMT). We investigated the role of MMP-2 and the effect of inhibition of MMPs on the development of renal fibrosis. Renal fibrosis was induced in MMP-2 wild-type (MMP-2⁺/⁺) mice by unilateral ureteral obstruction (UUO). Renal histopathology, EMT-associated molecules, and activity of MMP-2 and MMP-9 were examined during the development of interstitial fibrosis. UUO-renal fibrosis was also induced in MMP-2 deficient (MMP-2⁻/⁻) and MMP-2⁺/⁺ mice treated with minocycline (inhibitor of MMPs). In MMP-2⁺/⁺ mice, MMP-2 and MMP-9 were expressed in damaged tubules, and their activities increased in a time-dependent manner after UUO. Interstitial fibrosis was noted at day 14, with deposition of types III and I collagens and expression of markers of mesenchymal cells (S100A4, vimentin, α-smooth muscle actin, and heat shock protein-47) in damaged tubular epithelial cells, together with F4/80+ macrophage infiltration. Fibrotic kidneys expressed EMT-associated molecules (ILK, TGF-β1, Smad, Wnt, β-catenin, and Snail). In contrast, the kidneys of MMP-2⁻/⁻ mice and minocycline-treated MMP-2⁺/⁺ mice showed amelioration of renal fibrosis with reduced expression of markers of mesenchymal cells in tubular epithelial cells, inhibition of upregulated EMT-associated molecules, and suppression of macrophage infiltration. The results suggested that MMP-2 have a pathogenic role in renal interstitial fibrosis, possibly through the induction of EMT and macrophage infiltration. Inhibition of MMPs may be beneficial therapeutically in renal fibrosis.

MeSH terms

  • Animals
  • Collagen / metabolism
  • Epithelial Cells
  • Epithelial-Mesenchymal Transition*
  • Fibrosis / enzymology
  • Fibrosis / genetics
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Gene Expression Regulation
  • Histocytochemistry
  • Kidney Diseases / genetics
  • Kidney Diseases / metabolism*
  • Kidney Diseases / pathology
  • Kidney Tubules / chemistry
  • Kidney Tubules / pathology
  • Male
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Mice
  • Mice, Transgenic
  • Minocycline
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • Ureteral Obstruction / genetics
  • Ureteral Obstruction / metabolism*
  • Ureteral Obstruction / pathology


  • Matrix Metalloproteinase Inhibitors
  • RNA, Messenger
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100a4 protein, mouse
  • Collagen
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Minocycline