Evidence that Fe‐NTA‐induced renal prostaglandin F2α is responsible for hyperplastic response in kidney: Implications for the role of cyclooxygenase‐dependent arachidonic acid metabolism in renal tumor promotion

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Abstract
Oxidative stress in a tissue activates phospholipase A2 which releases free arachidonic acid. In addition, a low grade oxidative tone also stimulates the tissue cyclooxygenase activity. Cyclooxygenase‐dependent arachidonic acid metabolites such as PGF2α are known to play an important role in the development and maintenance of hyperplasia in skin in response to the application of tumor promoters. In this study we show that Fe‐NTA, an oxidant renal tumor promoter induces PGF2α which was maximum at 12 hours after Fe‐NTA treatment. However, at all time points studied, the elevated levels of PGF2α have been observed. As a result of the induction of PGF2α, the hyperplastic response can also be observed in the histopathology of the tissue. Additionally, an increased incorporation of [3H]thymidine in renal DNA has also been observed. Pretreatment of animals with indomethacin suppresses Fe‐NTA‐mediated hyperproliferation suggesting a role of cyclooxygenase in Fe‐NTA‐mediated stimulation of hyperplastic activity. The pretreatment of animals with the chain breaking antioxidants, Vit. E, BHA and BHT were only partially effective in inhibiting Fe‐NTA‐mediated PGF2α production, further suggesting a role of non‐free radical‐dependent mechanism in its production. Our data suggest that Fe‐NTA‐induced PGF2α through the activation of cyclooxygenase is responsible for the development and maintenance of hyperplasia in kidney.

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