EXPRESSION OF THE TRANSCRIPTIONAL REGULATOR EGR-1 IN EXPERIMENTAL GLOMERULONEPHRITIS - REQUIREMENT FOR MESANGIAL CELL-PROLIFERATION

The early growth response gene-1 (Egr-1), a zinc finger transcriptiona l regulator, was induced in a rat model of mesangioproliferative glome rulonephritis (GN). Northern blot analysis revealed a maximal 14.9-fol d increase in glomerular Egr-1 mRNA at day 6 of GN. By immunohistochem istry Egr-1 protein expression was demonstrated to be mainly confined to glomerular mesangial cells (MC). To test whether Egr-1 directly reg ulates MC proliferation, cultured MCs were stimulated with platelet-de rived growth factor (PDGF) after preincubation with different Egr-1 an tisense oligonucleotides (ASOs). PDGF-induced Egr-1 mRNA levels were i nhibited by up to 75% and protein levels by up to 91%. In addition Egr -1-specific ASOs blacked PDGF-induced rise in H-3-thymidine uptake hy 83% and almost completely abrogated increase in MC number. We conclude that Egr-1 induction is of critical importance far PDGF-induced mitog enic signaling in MCs, and inhibition of Egr-1 in vivo may offer an ap proach to oppose glomerular MC proliferation in glomerular inflammator y disease.