Dehydration activates an NF-kappa B-driven, COX2-dependent survival mechanism in renal medullary interstitial cells

Renal prostaglandin (PG) synthesis is mediated by cyclooxygenase-1 and -2 ( COX1 and COX2). After dehydration, the maintenance of normal renal function becomes particularly dependent upon PG synthesis. The present studies were designed to examine the potential link between medullary COX1 and COX2 exp ression in hypertonic stress. In response to water deprivation, COX2, but n ot COX1, mRNA levels increase significantly in the renal medulla, specifica lly in renal medullary interstitial cells (RMICs). Water deprivation also i ncreases renal NF-kappa B-driven reporter expression in transgenic mice. NF -kappa B activity and COX2 expression could be induced in cultured RMICs wi th hypertonic sodium chloride and mannitol, but not urea. RMIC COX2 express ion was also induced by driving NF-kappa B activation with a constitutively active I kappa B kinase alpha (IKK alpha). Conversely, introduction of a d ominant-negative I kappa B mutant reduced COX2 expression after hypertonici ty or IKK alpha induction. RMICs failed to survive hypertonicity when COX2 was downregulated using a COX2-selective antisense or blocked with the sele ctive nonsteroidal anti-inflammatory drug (NSAID) SC58236, reagents that di d not affect cell survival in isotonic media. In rabbits treated with SC582 36, water deprivation induced apoptosis of medullary interstitial cells in the renal papilla. These results demonstrate that water deprivation and hyp ertonicity activate NF-kappa B. The consequent increase in COX2 expression favors RMIC survival in hypertonic conditions. Inhibition of RMIC COX2 coul d contribute to NSAID-induced papillary injury.