EVIDENCE THAT FE-NTA-INDUCED RENAL PROSTAGLANDIN-F2-ALPHA IS RESPONSIBLE FOR HYPERPLASTIC RESPONSE IN KIDNEY - IMPLICATIONS FOR THE ROLE OFCYCLOOXYGENASE-DEPENDENT ARACHIDONIC-ACID METABOLISM IN RENAL TUMOR PROMOTION

Oxidative stress in a tissue activates phospholipase A(2) which releas es free arachidonic acid. In addition, a low grade oxidative tone also stimulates the tissue cyclooxygenase activity. Cyclooxygenase-depende nt arachidonic acid metabolites such as PGF(2) alpha are known to play an important role in the development and maintenance of hyperplasia i n skin in response to the application of tumor promoters. In this stud y we show that Fe-NTA, an oxidant renal tumor promoter induces PGF(2) alpha which was maximum at 12 hours after Fe-NTA treatment. However, a t all time points studied, the elevated levels of PGF(2) alpha have be en observed. As a result of the induction of PGF(2) alpha, the hyperpl astic response can also be observed in the histopathology of the tissu e. Additionally, an increased incorporation of [H-3]thymidine in renal DNA has also been observed. Pretreatment of animals with indomethacin suppresses Fe-NTA-mediated hyperproliferation suggesting a role of cy clooxygenase 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-med iated PGF(2) alpha production, further suggesting a role of non-free r adical-dependent mechanism in its production. Our data suggest that Fe -NTA-induced PGF(2) alpha through the activation of cyclooxygenase is responsible for the development and maintenance of hyperplasia in kidn ey.