title: Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy.
abstract: 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.
authors.affiliation: Department of Pathology-Analytic Human Pathology, Nippon Medical School, Tokyo, Japan.
authors.forename: Xuanyi
authors.initials: X
authors.lastname: Du
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Yukinari
authors.initials: Y
authors.lastname: Masuda
authors.forename: Naomi
authors.initials: N
authors.lastname: Kuwahara
authors.forename: Takashi
authors.initials: T
authors.lastname: Arai
authors.forename: Mitue
authors.initials: M
authors.lastname: Kataoka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Uchiyama
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaneko
authors.forename: Toshio
authors.initials: T
authors.lastname: Akimoto
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iino
authors.forename: Yuh
authors.initials: Y
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D004847:Epithelial Cells; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006651:Histocytochemistry; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000737:chemistry / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008822:Mice, Transgenic; D008911:Minocycline; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008911:Minocycline