Involvement of epimorphin in the repair of experimental renal fibrosis in mice.
Interaction between epithelial cells and mesenchymal cells is essential in normal organ morphogenesis and in tissue repair after injury. Epimorphin, a mesenchymal protein that regulates epithelial morphogenesis through epithelial-mesenchymal interactions, has recently attracted attention as an important modulator of tissue repair. In this study we analyzed the role of epimorphin in renal fibrosis. We first found a progressive increase in epimorphin expression corresponding to the progression of renal fibrosis in mice with unilateral ureteral obstruction (UUO). To determine whether this expression has a role in the repair or progression of renal fibrosis, we analyzed a model of renal fibrosis repair, the UUO-release (UUO-R) model. Epimorphin expression was increased at 3 and 7 days after the UUO-R rather than on the day of release, but was decreased at 21 days after the release. Inhibition of endogenous epimorphin with anti-epimorphin antibody (MC-1) significantly delayed the repair of fibrosis. When compared with normal-IgG-injected mice, MC-1-injected mice showed significantly decreased renal matrix metalloproteinase (MMP)-2 and MMP-9 expressions by western blotting and increased expression of TGF-beta and collagen-I mRNA by real-time RT-PCR. Recombinant epimorphin induced prominent increases in MMP-2 and MMP-9 activities in the culture media of renal interstitial fibroblasts in vitro. These findings indicate that epimorphin has a pivotal role in the repair of renal fibrosis by modulating both extracellular matrix (ECM) degradation and its production.
Yamada
Muneharu
M
Division of Nephrology, Department of Internal Medicine, Saitama, Japan.
Oda
Takashi
T
Higashi
Keishi
K
Kushiyama
Taketoshi
T
Yamakami
Kazuo
K
Sakurai
Yutaka
Y
Hirai
Yohei
Y
Yamamoto
Kojiro
K
Hyodo
Toshitake
T
Suzuki
Shigenobu
S
Miura
Soichiro
S
Kumagai
Hiroo
H
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018450:Disease Progression; D005355:Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic / Q000453:epidemiology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D014513:Ureter / Q000293:injuries / Q000473:pathology; D014517:Ureteral Obstruction / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology*
D000906:Antibodies; C504582:Epim protein, mouse; D008562:Membrane Glycoproteins