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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Carl
Marina
M
Med. Klinik IV, University Erlangen-Nürnberg, Erlangen, Germany.
Akagi
Yoshitaka
Y
Weidner
Sven
S
Isaka
Yoshitaka
Y
Imai
Enyu
E
Rupprecht
Harald D
HD
D000818:Animals; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D018014:Gene Transfer Techniques; D005920:Glomerular Mesangium / Q000473:pathology*; D015432:Glomerulonephritis, Membranoproliferative / Q000473:pathology* / Q000517:prevention & control* / Q000628:therapy; D017874:Immediate-Early Proteins; D007518:Isoantibodies; D008081:Liposomes; D008297:Male; D008938:Mitosis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D029082:Sendai virus / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D007518:Isoantibodies; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D020574:Proto-Oncogene Proteins c-sis; D014157:Transcription Factors; C035678:anti-Thy antibody