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J. Biol. Chem., Vol. 278, Issue 14, 12537-12545, April 4, 2003
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From the Division of Cellular and Molecular Pathology, Department
of Pathology, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania 15261
Tubular atrophy resulting from epithelial
cell loss is one of the characteristic features in the development of
chronic renal interstitial fibrosis. Although the trigger(s) and
mechanism for tubular cell loss remain undefined, the hyperactive
transforming growth factor (TGF)-
Transforming Growth Factor-
1 Potentiates Renal Tubular
Epithelial Cell Death by a Mechanism Independent of Smad
Signaling*
,, and
1 signaling has long been suspected
to play an active role. Here we demonstrate that although TGF-1 did
not induce cell death per se, it dramatically potentiated
renal tubular cell apoptosis initiated by other death cues in
vitro. Pre-incubation of human kidney epithelial cells (HKC) with
TGF-1 markedly promoted staurosporine-induced cell death in a time-
and dose-dependent manner. TGF-1 dramatically
accelerated the cleavage and activation of pro-caspase-9, but not
pro-caspase-8, in HKC cells. This event was followed by an accelerated
activation of pro-caspase-3. To elucidate the mechanism underlying
TGF-1 promotion of tubular cell death, we investigated the signaling
pathways activated by TGF-1. Both Smad-2 and p38 mitogen-activated
protein (MAP) kinase were rapidly activated by TGF-1, as
demonstrated by the early induction of phosphorylated Smad-2 and p38
MAP kinase, respectively. We found that overexpression of inhibitory
Smad-7 completely abolished Smad-2 phosphorylation and activation
induced by TGF-1 but did not inhibit TGF-1-induced apoptosis.
However, suppression of p38 MAP kinase with chemical inhibitor SC68376
not only abolished p38 MAP kinase phosphorylation but also obliterated
apoptosis induced by TGF-1. These results suggest that hyperactive
TGF-1 signaling potentiates renal tubular epithelial cell apoptosis by a Smad-independent, p38 MAP kinase-dependent mechanism.
*
This work was supported in part by National Institutes of
Health Grants DK-02611, DK-54922, and DK-61408 (to Y.L.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by postdoctoral fellowships from the American Heart
Association Pennsylvania-Delaware Affiliate.
§
To whom correspondence should be addressed: Dept. of Pathology,
University of Pittsburgh School of Medicine, S-405 Biomedical Science
Tower, 200 Lothrop St., Pittsburgh, PA 15261. Tel.: 412-648-8253; Fax:
412-648-1916; E-mail: liuy@msx.upmc.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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