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Role of oxygen radicals in phorbol myristate acetate-induced glomerular injury
Abstract:
Phorbol myristate acetate (PMA) is known to be a potent activator of neutrophils and macrophages resulting in the generation of large amounts of oxygen-free radicals by these cells. When injected into the left renal artery of 250 to 300 g male Sprague-Dawley rats, PMA caused significant proteinuria compared to control rats which received normal saline (35.4 +/- 4 mg/24 hr in PMA treated vs. 14.1 +/- 0.9 mg/24 hr in saline control, P less than 0.02). The proteinuria was associated with evidence of glomerular injury. These PMA-induced alterations were not prevented by complement depletion but were prevented by prior depletion of neutrophils. The coinstillation of catalase prevented the development of the proteinuria (catalase + PMA 12.7 +/- 2.3 mg/24 hr vs. PMA alone 38.2 +/- 5.7 mg/24 hr, P less than 0.001) suggesting that H2O2 and/or its metabolites derived from neutrophils were important in the PMA-induced proteinuria. In contrast, superoxide dismutase (SOD) had no effect. We conclude that, following the intra-arterial injection of PMA, neutrophil-derived hydrogen peroxide and/or its metabolic products are capable of causing acute proteinuria in association with morphological alterations in glomeruli of rats.
Insights
Phorbol myristate acetate (PMA) causes kidney injury and proteinuria in rats. Neutrophil-derived hydrogen peroxide, not superoxide, is the primary cause of this PMA-induced kidney damage.
Area of Science:
- Nephrology
- Immunology
- Toxicology
Background:
- Phorbol myristate acetate (PMA) activates neutrophils and macrophages, leading to oxygen-free radical generation.
- PMA administration is known to induce inflammatory responses in various tissues.
Purpose of the Study:
- To investigate the role of neutrophils and reactive oxygen species in PMA-induced kidney injury and proteinuria.
- To determine the specific reactive oxygen species responsible for PMA-induced glomerular damage.
Main Methods:
- Male Sprague-Dawley rats were injected with PMA into the left renal artery.
- Proteinuria levels were measured, and glomerular injury was assessed.
- Experiments involved complement depletion, neutrophil depletion, and coinstillation with catalase or superoxide dismutase (SOD).
Main Results:
- PMA injection caused significant proteinuria and glomerular injury compared to saline controls.
- Neutrophil depletion prevented PMA-induced proteinuria, while complement depletion did not.
- Catalase administration prevented proteinuria, whereas SOD had no effect, indicating H2O2's role.
Conclusions:
- Neutrophil-derived hydrogen peroxide is a key mediator of acute kidney injury and proteinuria induced by PMA.
- PMA-induced glomerular damage involves neutrophil activation and the subsequent release of reactive oxygen species.