TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy.
Progressive renal disease as a result of renal fibrosis is caused in part by an impairment of the proteolytic machinery that normally regulates matrix turnover. The goal of the present study was to determine whether genetic deficiency of tissue inhibitor of metalloproteinases-1 (TIMP-1) could attenuate interstitial fibrosis caused by unilateral ureteral obstruction (UUO). Groups of wild-type (Timp-1) mice and TIMP-1-deficient (timp-1) mice were killed after 3 and 14 d of UUO or sham operation. Timp-1 mRNA levels were significantly increased 37- and 19-fold in the wild-type mice 3 and 14 d, respectively, after UUO operation. Matrix metalloproteinase-9 (MMP-9) activity fell in all UUO groups but remained significantly higher in the timp-1 group compared with the Timp-1 group. The degree of interstitial fibrosis (kidney collagen content and percentage of tubulointerstitial area stained with picrosirius red and collagen III) was significantly increased 14 d after UUO operation, but there was no difference between the Timp-1 and timp-1 groups. Many features of the fibrogenic response were similar between the Timp-1 and timp-1 groups, including the number of myofibroblasts and the induction of genes encoding procollagen III, fibronectin, and transforming growth factor-beta. After UUO operation, renal mRNA levels for Timp-3 and plasminogen activator inhibitor-1 were significantly higher in the TIMP-1-deficient mice. The results of this study show that elimination of TIMP-1 alone does not alter the severity of interstitial fibrosis. These findings may be due to compensation by other protease inhibitors such as TIMP-2, TIMP-3, and/or plasminogen activator inhibitor-1 or to the possibility that inhibition of intrinsic MMP activity does not constitute a profibrogenic event in the kidney.
Kim
Heungsoo
H
The Children's Hospital and Regional Medical Center, University of Washington, Seattle, Washington.
Oda
Takashi
T
The Children's Hospital and Regional Medical Center, University of Washington, Seattle, Washington.
López-Guisa
Jesús
J
The Children's Hospital and Regional Medical Center, University of Washington, Seattle, Washington.
Wing
Diane
D
The Children's Hospital and Regional Medical Center, University of Washington, Seattle, Washington.
Edwards
Dylan R
DR
School of Biological Sciences, University of East Anglia, Norwich, England.
Soloway
Paul D
PD
Roswell Park Cancer Institute, Department of Molecular and Cellular Biology, Buffalo, New York.
Eddy
Allison A
AA
The Children's Hospital and Regional Medical Center, University of Washington, Seattle, Washington.
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001835:Body Weight; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D018093:Gelatinases / Q000235:genetics; D015870:Gene Expression; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D009130:Muscle, Smooth / Q000473:pathology; D009929:Organ Size; D011347:Procollagen / Q000235:genetics; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D014517:Ureteral Obstruction / Q000473:pathology*
D011347:Procollagen; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D018093:Gelatinases; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9