Selective targeting of cyclooxygenase-2 reveals its role in renal medullary interstitial cell survival

Renal medullary interstitial cells (MICs) are a major site of cyclooxygenas e (COX)-mediated PG synthesis. These studies examined the role of COX in MI C survival. Immunoblot and nuclease protection demonstrate that cultured MI Cs constitutively express COX2, with Little constitutive COX1 expression. S C-58236, a COX2-selective inhibitor, but not SC-58560, a COX1 inhibitor, pr eferentially blocks PGE(2) synthesis in MICs. Transduction with a COX2 anti sense adenovirus reduced MIC COX2 protein expression and also decreased PGE 2 production. Antisense downregulation of COX2 was associated with MIC deat h, whereas a control adenovirus was without effect. Similarly the COX2-sele ctive inhibitor SC-58236 (30 mu M) and several nonselective COX-inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac, ibuprofe n, and indomethacin, all caused MIC death. In contrast, SC-58560, a COX1-se lective inhibitor, was 100-fold less potent for inducing MIC death than its structural congener SC-58236. NSAID-induced MIC death was associated with DNA laddering and nuclear fragmentation, consistent with apoptosis. These r esults suggest that COX2 plays an important role in MIC survival. COX2 inhi bition may contribute to NSAID-associated injury of the renal medulla.