Role of membrane-type matrix metalloproteinase 1 (MT-1-MMP), MMP-2, and its inhibitor in nephrogenesis.
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.
Kanwar
Y S
YS
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611, USA. y-kanwar@nwu.edu
Ota
K
K
Yang
Q
Q
Wada
J
J
Kashihara
N
N
Tian
Y
Y
Wallner
E I
EI
D000375:Aging; D000818:Animals; D005314:Embryonic and Fetal Development; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D007668:Kidney / Q000196:embryology* / Q000201:enzymology / Q000254:growth & development*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D020782:Matrix Metalloproteinases / Q000235:genetics*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D051379:Mice; D008813:Mice, Inbred ICR; D009024:Morphogenesis / Q000187:drug effects; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D014158:Transcription, Genetic
D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2