Volume 271, Number 45, Issue of November 8, 1996 pp. 28306-28310
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Transcription Factor Egr-1 Regulates Glomerular Mesangial Cell Proliferation

(Received for publication, April 8, 1996, and in revised form, August 9, 1996)

Gerhard Hofer , Claudia Grimmer , Vikas P. Sukhatme ^¶ , R. Bernd Sterzel and Harald D. Rupprecht

From the  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

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.

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