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An oral platelet-activating factor antagonist, Ro-24-4736, protects the rat kidney from ischemic injury
K J Kelly1, N E Tolkoff-Rubin, R H Rubin
1Medical Service, Massachusetts General Hospital, Boston, USA.
Abstract:
The role of platelet-activating factor (PAF) in ischemic acute renal failure was evaluated by administering an oral PAF antagonist (Ro-24-4736) to rats prior to or after interruption of blood flow to both kidneys for 30 min. In animals treated with the PAF antagonist prior to ischemia, renal function was less impaired and histological abnormalities was less pronounced when compared with postischemic kidneys from vehicle-treated animals. Serum creatinine (mg/ dl) 24 h following renal ischemia was 1.58 +/- 0.17 in the PAF antagonist-treated rats compared with 2.19 +/- 0.15 in rats given placebo (P < 0.01). There was less necrosis in the outer medulla of kidneys of PAF antagonist-treated animals (P < 0.01). Tissue myeloperoxidase activity at 48 and 72 h postischemia was lower in kidneys of PAF antagonist-treated rats (P < 0.05). The PAF antagonist was also protective when administered 30 min but not 2 h following the ischemic insult. The coincident use of anti-intercellular adhesion molecule-1 monoclonal antibody did not confer additional protection over that observed with the oral PAF antagonist alone. These data suggest that PAF contributes to the pathophysiology of renal ischemic injury, perhaps by its effects on leukocyte-endothelial interactions. An orally active PAF antagonist can protect against the development of ischemic acute renal failure.
Insights
Platelet-activating factor (PAF) contributes to acute kidney injury. An oral PAF antagonist protected rats from kidney damage and reduced inflammation, suggesting a therapeutic role in preventing renal failure.
Area of Science:
- Nephrology
- Pharmacology
- Pathophysiology
Background:
- Platelet-activating factor (PAF) is implicated in inflammatory processes.
- The role of PAF in ischemic acute renal failure (ARF) requires further elucidation.
Purpose of the Study:
- To evaluate the therapeutic potential of an oral PAF antagonist in a rat model of ischemic ARF.
- To investigate the protective effects of PAF inhibition on renal function and histology following ischemia-reperfusion injury.
Main Methods:
- Administration of an oral PAF antagonist (Ro-24-4736) or vehicle to rats before or after a 30-minute bilateral renal ischemia.
- Assessment of renal function via serum creatinine levels.
- Histological examination of kidney tissue for necrosis.
- Measurement of tissue myeloperoxidase activity as an indicator of neutrophil infiltration.
Main Results:
- Pre-treatment with the PAF antagonist significantly reduced renal impairment and histological damage compared to controls.
- Serum creatinine levels were significantly lower in antagonist-treated rats 24 hours post-ischemia (1.58 vs. 2.19 mg/dL).
- Reduced outer medullary necrosis and lower myeloperoxidase activity were observed in kidneys of antagonist-treated animals.
Conclusions:
- PAF plays a significant role in the pathophysiology of ischemic acute renal failure.
- An orally active PAF antagonist demonstrates protective effects against renal ischemic injury.
- PAF inhibition may offer a therapeutic strategy for preventing or mitigating ischemic ARF, potentially by modulating leukocyte-endothelial interactions.