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

被引:95
作者
Hao, CM
Kömhoff, M
Guan, YF
Redha, R
Breyer, MD
机构
[1] Vet Affairs Med Ctr, Dept Med, Div Nephrol, Nashville, TN 37212 USA
[2] Vet Affairs Med Ctr, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA
[3] Vanderbilt Univ, Sch Med, Nashville, TN 37232 USA
关键词
papillary necrosis; adenovirus; antisense; analgesic nephropathy;
D O I
10.1152/ajprenal.1999.277.3.F352
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Renal medullary interstitial cells (MICs) are a major site of cyclooxygenase (COX)-mediated PG synthesis. These studies examined the role of COX in MIC survival. Immunoblot and nuclease protection demonstrate that cultured MICs constitutively express COX2, with Little constitutive COX1 expression. SC-58236, a COX2-selective inhibitor, but not SC-58560, a COX1 inhibitor, preferentially blocks PGE(2) synthesis in MICs. Transduction with a COX2 antisense adenovirus reduced MIC COX2 protein expression and also decreased PGE2 production. Antisense downregulation of COX2 was associated with MIC death, whereas a control adenovirus was without effect. Similarly the COX2-selective inhibitor SC-58236 (30 mu M) and several nonselective COX-inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac, ibuprofen, and indomethacin, all caused MIC death. In contrast, SC-58560, a COX1-selective 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 results suggest that COX2 plays an important role in MIC survival. COX2 inhibition may contribute to NSAID-associated injury of the renal medulla.
引用
收藏
页码:F352 / F359
页数:8
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