TRANSCRIPTION FACTOR EGR-1 REGULATES GLOMERULAR MESANGIAL CELL-PROLIFERATION

Increase of glomerular mesangial cells (MCs) is a prominent histopatho logical finding in many types of glomerulonephritis. We have shown pre viously that expression of the zinc-finger transcription factor, early growth response gene-1 (egr-1), is closely correlated with the prolif eration of cultured MCs. To elucidate whether Egr-1 is required for MC proliferation, we inhibited serum-induced Egr-1 expression by phospho thioate-modified antisense oligonucleotides (ODNs), Uptake of antisens e ODNs into ASCs was demonstrated, and five different egr-1 antisense ODNs were tested for their impact on serum-induced egr-1 mRNA and prot ein levels and on MC growth. The most potent egr-1 antisense ODN inhib ited serum-induced egr-1 mRNA by 68%, protein induction by 58%, and MC replication as measured by [H-3]thymidine uptake and cell counts by 7 8 and 46%, respectively. The effects of antisense ODNs on MC growth co rrelated closely with their ability to inhibit Egr-1 protein, ODNs act ed in a dose-dependent manner, the minimal effective concentration bei ng 1 mu M. Control ODNs had no significant effects. In addition, antis ense ODNs against egr-1 potently inhibited endothelin-1-induced Egr-1 expression and MC growth, Heparin, a known inhibitor of MC growth, sup pressed serum-induced [H-3]thymidine uptake by 39% and egr-1 mRNA expr ession by 44%. We conclude that Egr-1 is an essential part of the mito genic signal transduction cascade in cultured MCs.