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Effect of antisense TGF-beta1 oligodeoxynucleotides in streptozotocin- induced diabetic rat kidney
Hyo Soon Jeong1, Kwan Kyu Park, Kwan Kyu Park
1Department of Anatomy, Keimyung University School of Medicine, Daegu, Korea.
Abstract:
Transforming growth factor (TGF)-beta1 is an important fibrogenic factor that is involved in the pathogenesis of diabetic nephropathy. We evaluated the effect of circular antisense TGF-beta1 oligodeoxynucleotides (ODNs) on the TGF-beta1 expression in the rat mesangial cell culture and in streptozotocin (STZ)-induced diabetic rats. Circular antisense TGF-beta1 ODNs were found to be stable in rat serum, significantly decreasing TGF-beta1 mRNA expression compared with linear antisense ODNs in the rat mesangial cell culture. Circular antisense TGF-beta1 ODNs were introduced into the tail vein of normal rats using hemagglutinating virus of Japan (HVJ)-liposome-mediated gene transfer method and were confirmed to be delivered effectively into the kidney, liver, lungs, and spleen. To inhibit the overexpression of TGF-beta1 in diabetic kidneys, we introduced circular antisense TGF-beta1 ODNs into the STZ-induced diabetic rats. On day 13 after circular antisense TGF-beta1 ODNs injection, TGF-beta1 mRNA and protein expression markedly decreased and urinary TGF-beta1 excretion rate also dropped in the circular antisense TGF-beta1 ODNs-treated diabetic rats. These results suggest that circular antisense TGF-beta1 ODNs may be a useful tool for developing new therapeutic application for progressive diabetic nephropathy.
Insights
Circular antisense oligodeoxynucleotides (ODNs) targeting transforming growth factor-beta1 (TGF-beta1) effectively reduced TGF-beta1 expression in diabetic nephropathy models. This suggests a potential new therapy for progressive diabetic kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Diabetic nephropathy is characterized by fibrosis, with transforming growth factor-beta1 (TGF-beta1) as a key fibrogenic mediator.
- Overexpression of TGF-beta1 contributes significantly to the pathogenesis of diabetic kidney disease.
Purpose of the Study:
- To evaluate the efficacy of circular antisense TGF-beta1 oligodeoxynucleotides (ODNs) in inhibiting TGF-beta1 expression.
- To assess the therapeutic potential of circular antisense TGF-beta1 ODNs in a rat model of diabetic nephropathy.
Main Methods:
- In vitro: Rat mesangial cell culture treated with circular and linear antisense TGF-beta1 ODNs.
- In vivo: Hemagglutinating virus of Japan (HVJ)-liposome-mediated gene transfer of circular antisense TGF-beta1 ODNs into streptozotocin (STZ)-induced diabetic rats.
- Analysis of TGF-beta1 mRNA and protein expression, and urinary TGF-beta1 excretion.
Main Results:
- Circular antisense TGF-beta1 ODNs demonstrated stability in rat serum and superior inhibition of TGF-beta1 mRNA compared to linear ODNs in vitro.
- Effective delivery of circular antisense TGF-beta1 ODNs to multiple organs, including the kidney, was confirmed.
- In diabetic rats, circular antisense TGF-beta1 ODNs significantly reduced TGF-beta1 mRNA and protein levels, along with urinary TGF-beta1 excretion.
Conclusions:
- Circular antisense TGF-beta1 ODNs are stable and effectively inhibit TGF-beta1 expression in vitro and in vivo.
- This approach shows promise as a therapeutic strategy for managing progressive diabetic nephropathy by targeting TGF-beta1 overexpression.
