Role of membrane-type matrix metalloproteinase 1 (MT-1-MMP), MMP-2, and its inhibitor in nephrogenesis

Am J Physiol. 1999 Dec;277(6):F934-47. doi: 10.1152/ajprenal.1999.277.6.F934.

Abstract

Extracellular matrix (ECM) proteins, their integrin receptors, and matrix metalloproteinases (MMPs), the ECM-degrading enzymes, are believed to be involved in various biological processes, including embryogenesis. In the present study, we investigated the role of membrane type MMP, MT-1-MMP, an activator pro-MMP-2, in metanephric development. Also, its relationship with MMP-2 and its inhibitor, TIMP-2, was studied. Since mRNAs of MT-1-MMP and MMP-2 are respectively expressed in the ureteric bud epithelia and mesenchyme, they are ideally suited for juxtacrine/paracrine interactions during renal development. Northern blot analyses revealed a single approximately 4.5-kb mRNA transcript of MT-1-MMP, and its expression was developmentally regulated. Inclusion of MT-1-MMP antisense oligodeoxynucleotide (ODN) in the culture media induced dysmorphogenetic changes in the embryonic metanephros. MMP-2 antisense ODN also induced similar changes, but they were relatively less; on the other hand TIMP-2 antisense ODN induced a mild increase in the size of explants. Concomitant exposure of MT-1-MMP and MMP-2 antisense ODNs induced profound alterations in the metanephroi. Treatment of TIMP-2 antisense ODN to metanephroi exposed to MT-1-MMP/MMP-2 antisense notably restored the morphology of the explants. Specificity of the MT-1-MMP antisense ODN was reflected in the selective decrease in its mRNA and protein expression. The MT-1-MMP antisense ODN also resulted in a failure in the activation of pro-MMP-2 to MMP-2. These findings suggest that the trimacromolecular complex of MT-1-MMP:MMP-2:TIMP-2 modulates the organogenesis of the metanephros, conceivably by mediating paracrine/juxtacrine epithelial:mesenchymal interactions.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging
  • Animals
  • Embryonic and Fetal Development
  • Gene Expression Regulation, Developmental* / drug effects
  • Gene Expression Regulation, Enzymologic
  • Gestational Age
  • Kidney / embryology*
  • Kidney / enzymology
  • Kidney / growth & development*
  • Matrix Metalloproteinase 2 / genetics*
  • Matrix Metalloproteinases / genetics*
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases*
  • Mice
  • Mice, Inbred ICR
  • Morphogenesis / drug effects
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Organ Culture Techniques
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Transcription, Genetic*

Substances

  • Oligodeoxyribonucleotides, Antisense
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinases
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2