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Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo
Y Maeshima1, N Kashihara, T Yasuda
1Department of Medicine III, Okayama University Medical School, Okayama 700, Japan.
Abstract:
The transcription factor E2F coordinately activates several cell cycle-regulatory genes. We attempted to inhibit the proliferation of mesangial cells in vitro and in vivo by inhibiting E2F activity using a 25-bp decoy oligodeoxynucleotide that contained consensus E2F binding site sequence (E2F-decoy) as a competitive inhibitor. The decoy's effect on human mesangial cell proliferation was evaluated by [3H]thymidine incorporation. The E2F decoy inhibited proliferation in a concentration-dependent manner, whereas a mismatch control oligodeoxynucleotide had little effect. Electrophoretic mobility shift assays demonstrated that the decoy's inhibitory effect was due to the binding of the decoy oligodeoxynucleotide to E2F. The effect of the E2F decoy was then tested in a rat anti-Thy 1.1 glomerulonephritis model. The E2F decoy oligodeoxynucleotide was introduced into the left kidney 36 h after the induction of glomerulonephritis. The administration of E2F decoy suppressed the proliferation of mesangial cells by 71%. Furthermore, treatment with the E2F decoy inhibited the glomerular expression of proliferating cell nuclear antigen at the protein level as well as the mRNA level. These findings indicate that decoy oligonucleotides can suppress the activity of the transcription factor E2F, and may thus have a potential in treating glomerulonephritis.
Insights
Researchers inhibited mesangial cell proliferation using an E2F decoy oligodeoxynucleotide. This approach effectively suppressed E2F activity and shows potential for treating glomerulonephritis.
Area of Science:
- Molecular Biology
- Nephrology
- Gene Regulation
Background:
- The transcription factor E2F regulates cell cycle genes, making it a target for controlling cell proliferation.
- Mesangial cell proliferation is a key factor in the pathogenesis of glomerulonephritis.
Purpose of the Study:
- To investigate the efficacy of an E2F decoy oligodeoxynucleotide in inhibiting mesangial cell proliferation in vitro and in vivo.
- To assess the potential of E2F decoy therapy for glomerulonephritis.
Main Methods:
- In vitro studies used [3H]thymidine incorporation to measure human mesangial cell proliferation inhibition by E2F decoy oligodeoxynucleotides.
- Electrophoretic mobility shift assays confirmed the binding of E2F decoy to E2F.
- In vivo studies utilized a rat anti-Thy 1.1 glomerulonephritis model, administering the E2F decoy to the kidney.
Main Results:
- The E2F decoy significantly inhibited mesangial cell proliferation in a concentration-dependent manner in vitro.
- In vivo, E2F decoy administration suppressed mesangial cell proliferation by 71% in the glomerulonephritis model.
- Glomerular expression of proliferating cell nuclear antigen (PCNA) was reduced at both protein and mRNA levels post-treatment.
Conclusions:
- Decoy oligodeoxynucleotides effectively suppress E2F transcription factor activity.
- E2F decoy therapy demonstrates therapeutic potential for managing glomerulonephritis by inhibiting key proliferative pathways.
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