Specific inhibition of Egr-1 prevents mesangial cell hypercellularity in experimental nephritis

• Published in: Kidney international Vol. 63; no. 4; pp. 1302 - 1312
• Main Authors: Carl, Marina, Akagi, Yoshitaka, Weidner, Sven, Isaka, Yoshitaka, Imai, Enyu, Rupprecht, Harald D.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2003; Nature Publishing; Elsevier Limited
• Subjects: Animals; antisense; Biological and medical sciences; Cell Division; DNA-Binding Proteins - genetics; Early Growth Response Protein 1; Gene Transfer Techniques; Glomerular Mesangium - pathology; Glomerulonephritis; Glomerulonephritis, Membranoproliferative - pathology; Glomerulonephritis, Membranoproliferative - prevention & control; Glomerulonephritis, Membranoproliferative - therapy; Hemagglutinating virus of Japan; immediate early gene; Immediate-Early Proteins; Isoantibodies; liposome; Liposomes; Male; Medical sciences; mesangioproliferative glomerulonephritis; Mitosis; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Oligonucleotides, Antisense - pharmacology; Proto-Oncogene Proteins c-sis - genetics; Rats; Rats, Sprague-Dawley; Sendai virus - genetics; transcription factor; Transcription Factors - genetics; transcription factor; immediate early gene; mesangioproliferative glomerulonephritis; liposome; antisense; Kidney disease; Immunohistochemistry; Proliferative glomerulonephritis; Urinary system disease; Pathophysiology; Rat; Rodentia; Exploration; Kidney; Pathology; Vertebrata; Mammalia; Animal; Transcription factor
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1046/j.1523-1755.2003.00865.x

Specific inhibition of Egr-1 prevents mesangial cell hypercellularity in experimental nephritis. Mesangial cell proliferation is a frequent finding in glomerulonephritis. In cultured mesangial cells, we demonstrated that inhibition of the zinc finger transcription factor, early growth response gene-1 (Egr-1), by specific antisense oligonucleotides (AS ODN) blocks mesangial cell proliferation. Therefore, we here investigated the effect of Egr-1 inhibition on the course of an experimental mesangioproliferative glomerulonephritis in vivo. On day 3 after induction of anti-Thy-1.1 nephritis, specific glomerular oligonucleotide transfer was achieved by injection of an oligonucleotide/hemagglutinating virus of Japan/liposome mixture into the left renal artery. The right kidney was left untreated. Induction of nephritis led to a sixfold induction of Egr-1 protein on day 6 of disease. This increase in Egr-1 expression was reduced by 48% in the left kidney by transfer of specific AS ODN. In parallel, the increases in glomerular cellularity, number of mitoses, and glomerular tuft area observed in day 6 nephritic animals were inhibited in the left kidney by 60%, 53%, and 50%, respectively. Changes in the right kidney were not significantly influenced. Likewise, control oligonucleotides showed no effect. Finally, the expression of platelet-derived growth factor-B (PDGF-B), a known target gene of Egr-1, was repressed by transfer of specific AS ODN against Egr-1. We conclude that the transcription factor Egr-1 plays a critical role for mesangial cell proliferation in vivo. Interfering with the induction of Egr-1 or with its target genes could give rise to novel therapeutic principles in mesangioproliferative glomerulonephritis.