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-dependent fibrogenesis in mesangial
cells
Division of Nephrology and Hypertension, Research and Education Institute at Harbor-UCLA Medical Center, Torrance, California 90502
Exogenous administration of
recombinant human bone morphogenetic protein (BMP)-7 was recently shown
to ameliorate renal glomerular and interstitial fibrosis in rodents
with experimental renal diseases. We tested the hypothesis that BMP7
functions by antagonizing profibrogenic events that are induced by
transforming growth factor (TGF)-
in cultured mesangial cells.
Incubation of murine mesangial cells with TGF- (50-200 pM)
increased cell-associated collagen type IV and fibronectin, soluble
collagen type IV, thrombospondin, and connective tissue growth factor
(CTGF). Coincubation with recombinant human BMP7 (200 pM) reduced the
increase of these ECM proteins and CTGF. The changes in
collagen type IV and fibronectin proteins occurred without concomitant
changes in collagen type 
1IV and fibronectin mRNA
levels, suggesting that TGF- and BMP7 act primarily by affecting ECM
protein degradation. Indeed, TGF- decreases the levels and activity
of matrix metalloprotease (MMP)-2, the major metalloprotease that is
secreted by mesangial cells. Moreover, BMP7 inhibits TGF--induced
activation of MMP2. Because TGF- reduces the activity of MMPs
through increasing plasminogen activator inhibitor (PAI)-1, we tested
whether BMP7 interferes with this TGF- effect. BMP7 reduces, by
about two-thirds, the activation of a PAI-1 promoter/luciferase
reporter in cells stably transfected with this construct. The findings
from these studies indicate that BMP7 reduces TGF--induced ECM
protein accumulation in cultured mesangial cells primarily by
maintaining levels and activity of MMP2 partially through prevention of
TGF--dependent upregulation of PAI-1.
bone morphogenetic protein 7; transforming growth factor-; kidney fibrosis; matrix metalloprotease-2; plasminogen activator
inhibitor-1
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