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(Received for publication, April 8, 1996, and in revised form, August 9, 1996)
From the Increase of glomerular mesangial cells (MCs) is a
prominent histopathological finding in many types of
glomerulonephritis. We have shown previously that expression of the
zinc-finger transcription factor, early growth response gene-1
(egr-1), is closely correlated with the proliferation of
cultured MCs. To elucidate whether Egr-1 is required for MC
proliferation, we inhibited serum-induced Egr-1 expression by
phosphothioate-modified antisense oligonucleotides (ODNs). Uptake of
antisense ODNs into MCs was demonstrated, and five different
egr-1 antisense ODNs were tested for their impact on
serum-induced egr-1 mRNA and protein levels and on MC
growth. The most potent egr-1 antisense ODN inhibited
serum-induced egr-1 mRNA by 68%, protein induction by
58%, and MC replication as measured by [3H]thymidine
uptake and cell counts by 78 and 46%, respectively. The effects of
antisense ODNs on MC growth correlated closely with their ability to
inhibit Egr-1 protein. ODNs acted in a dose-dependent
manner, the minimal effective concentration being 1 µM.
Control ODNs had no significant effects. In addition, antisense ODNs
against egr-1 potently inhibited endothelin-1-induced Egr-1
expression and MC growth. Heparin, a known inhibitor of MC growth,
suppressed serum-induced [3H]thymidine uptake by 39% and
egr-1 mRNA expression by 44%. We conclude that Egr-1
is an essential part of the mitogenic signal transduction cascade in
cultured MCs.
Volume 271, Number 45,
Issue of November 8, 1996
pp. 28306-28310
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
and
Medizinische Klinik IV der Universität
Erlangen-Nürnberg, Nephrologische Forschungslabors,
Loschgestrasse 8, 91054 Erlangen, Germany and the ¶ Department of
Medicine, Harvard Medical School and Beth Israel Hospital, Boston,
Massachusetts 02215
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