EFFECT OF PAPILLOTOXIC AGENTS ON EXPRESSION OF CYCLOOXYGENASE ISOFORMS IN THE RAT-KIDNEY

Inhibition of renal vasodilatory prostaglandins (PGs) and secondary is chemia due to inhibition of cyclooxygenase (COX) activity has been sug gested as a possible mechanism for development of analgesic-related re nal papillary necrosis (RPN) in rats. Recently, it has been shown that COX exists in two related but unique isoforms, COX-1 and COX-2. It is unclear what potential roles these isoforms play in the maintenance o f blood flow in the renal papilla or genesis of RPN. We evaluated the effect of 2 papillotoxic agents, including a nonsteroidal anti-inflamm atory drug, indomethacin, and a chemical agent, 2-bromoethanamine hydr obromide (2-BEA), on COX-1 and COX-2 in the renal papilla as a means o f assessing what changes occur in the expression of these isoforms dur ing the development of RPN. Female Wistar rats approximate to 10-17 wk old were treated with either indomethacin (75 mg/kg, single dose, or 10 mg/kg/day for 5 days) or 2-BEA (100 mg/kg/day for 4 days) to create lesions of RPN. In this study, a single 75-mg/kg dose of indomethacin did not cause light microscopic changes of RPN. However, RPN was obse rved in animals administered indomethacin at 10 mg/kg/day for 1 wk or 2-BEA for 5 days. The immunohistochemical analyses of kidneys showed t hat both COX-1 and COX-2 were present in the renal papilla of control rats. In animals treated with indomethacin (75 mg/kg), a slight to mod erate decrease in both isoforms was observed in essentially normal ren al papillary cells within 2 hr, that was followed by an increase in CO X-2 immunoreactivity in the renal papilla, macula densa, and thick asc ending limbs (both 10- and 75-mg/kg animals). This COX-2 immunoreactiv ity was greatest in animals with concomitant indomethacin-induced gast rointestinal injury, suggesting a possible role of inflammatory cytoki nes in COX-2 induction. No changes in the expression of COX isoforms i n the intact papilla occurred as a result of 2-BEA; however, cells und ergoing degeneration and necrosis lost immunoreactivity to both COX is oforms. The possible mechanism that leads to an initial decrease in CO X immunoreactivity in indomethacin-treated animals is not known; howev er, a reversible ultrastructural change in the papillary cells cannot be ruled out. This decrease in COX isoforms in the renal papilla may c ontribute to the development of RPN through the loss of vasodilatory P Gs.