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Antisense oligonucleotides for ICAM-1 attenuate reperfusion injury and renal failure in the rat
H Haller1, D Dragun, A Miethke
1Franz Volhard Clinic, Max Delbrück Center for Molecular Medicine, Virchow Klinikum, Humboldt University of Berlin, Germany.
Abstract:
The leukocyte adhesion molecule ICAM-1 is implicated in ischemic renal reperfusion injury. We tested the utility of an ICAM-1 antisense oligodeoxyribonucleotide (ODN) with lipofectin, six hours prior to 30 minutes of bilateral renal ischemia in the rat. We measured ICAM-1 expression by immunohistochemistry and Western blot. Our antisense ODN showed a specific ICAM-1 surface expression inhibition in vitro. We then assessed ICAM-1 expression, leukocyte infiltration, serum creatinine, serum urea concentration, and renal histology in rats subjected to renal ischemia and controls. Serum creatinine and urea concentrations 12 and 24 hours post-ischemia were increased in saline treated and reverse ODN treated rats, compared to antisense ODN treated or sham operated rats (P < 0.05). Western blotting showed decreased ICAM-1 protein in antisense ODN-treated kidneys, compared to reverse ODN treated and saline treated ischemic controls (P < 0.05). Antisense ODN also ameliorated the ischemia-induced infiltration of granulocytes and macrophages (P < 0.05), and resulted in less cortical renal damage as assessed by a quantitative pathological grading scale (P < 0.05), compared to reverse ODN or saline treatment. Thus, antisense ODN for ICAM-1 protected the kidney against ischemic renal failure. The clinical applicability of these findings extends beyond ischemic acute renal failure.
Insights
An antisense oligodeoxyribonucleotide (ODN) targeting ICAM-1 protected rat kidneys from ischemic injury. This treatment reduced inflammation and improved kidney function after ischemia, suggesting a potential therapy for acute renal failure.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Ischemic renal reperfusion injury is a significant clinical problem.
- Leukocyte adhesion molecule ICAM-1 plays a key role in this injury process.
- Targeting ICAM-1 offers a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the efficacy of an ICAM-1 antisense oligodeoxyribonucleotide (ODN) in preventing ischemic renal injury in rats.
- To assess the impact of ICAM-1 inhibition on renal function, histology, and inflammatory cell infiltration.
Main Methods:
- Rats were treated with ICAM-1 antisense ODN or control ODN/saline six hours before bilateral renal ischemia.
- ICAM-1 expression was measured by immunohistochemistry and Western blot.
- Renal function was assessed by serum creatinine and urea levels.
- Leukocyte infiltration and renal histology were evaluated post-ischemia.
Main Results:
- Antisense ODN significantly reduced ICAM-1 protein expression in ischemic kidneys.
- Treatment with antisense ODN ameliorated the increase in serum creatinine and urea levels.
- Reduced infiltration of granulocytes and macrophages was observed in antisense ODN-treated kidneys.
- Histological analysis showed less cortical renal damage in the antisense ODN group.
Conclusions:
- ICAM-1 antisense ODN effectively protects the kidney against ischemic renal failure in a rat model.
- This therapeutic approach reduces inflammation and preserves renal function post-ischemia.
- The findings suggest potential clinical applicability for ICAM-1 targeted therapies in acute renal failure and other related conditions.