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J. Biol. Chem., Vol. 277, Issue 44, 41725-41735, November 1, 2002
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From the Departments of The molecular mechanism(s) by which high glucose
induces fibronectin expression via G-protein activation in the kidney
are largely unknown. This investigation describes the effect of high glucose (HG) on a small GTP-binding protein, Rap1b, expression and
activation, and the relevance of protein kinase C (PKC) and Raf
pathways in fibronectin synthesis in cultured renal glomerular mesangial cells (MCs). In vivo experiments revealed a
dose-dependent increase in Rap1b expression in glomeruli of
diabetic rat kidneys. Similarly, in vitro exposure of MCs
to HG led to an up-regulation of Rap1b with concomitant increase in
fibronectin (FN) mRNA and protein expression. The up-regulation of
Rap1b mRNA was mitigated by the PKC inhibitors, calphostin C, and
bisindolymaleimide, while also reducing HG- induced FN expression in
non-transfected MCs. Overexpression of Rap1b by transfection with
pcDNA 3.1/Rap1b in MCs resulted in the stimulation of FN synthesis;
however, the PKC inhibitors had no significant effect in
reducing FN expression in Rap1b-transfected MCs.
Transfection of Rap1b mutants S17N (Ser
High Glucose Stimulates Synthesis of Fibronectin via a Novel
Protein Kinase C, Rap1b, and B-Raf Signaling Pathway*
,,, and§¶
Pathology and
§ Medicine, Northwestern University Medical School,
Chicago, Illinois 60611
Asn) or T61R (Thr Arg) in MCs inhibited the HG-induced increased FN synthesis. B-Raf
and Raf-1 expression was investigated to assess whether Rap1b effects
are mediated via the Raf pathway. B-Raf, and not Raf-1, expression was
increased in MCs transfected with Rap1b. HG also caused activation of
Rap1b, which was largely unaffected by anti-platelet-derived growth
factor (PDGF) antibodies. HG-induced activation of Rap1b was specific,
since Rap2b activation and expression of Rap2a and Rap2b were
unaffected by HG. These findings indicate that hyperglycemia and
HG cause an activation and up-regulation of Rap1b in renal glomeruli
and in cultured MCs, which then stimulates FN synthesis. This effect
appears to be PKC-dependent and PDGF-independent, but
involves B-Raf, suggesting a novel PKC-Rap1b-B-Raf pathway responsible for HG-induced increased mesangial matrix
synthesis, a hallmark of diabetic nephropathy.
*
This work was supported by National Institutes of Health
Grants DK28492, DK60635, and HL063407.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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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