Intracellular prostaglandin E2 contributes to hypoxia-induced proximal tubular cell death

Proximal tubular cells (PTC) are particularly vulnerable to hypoxia-induced apoptosis, a relevant factor for kidney disease. We hypothesized here that PTC death under hypoxia is mediated by cyclo-oxygenase (COX-2)-dependent production of prostaglandin E(2) (PGE(2)), which was confirmed in human proximal tubular HK-2 cells because hypoxia (1% O(2))-induced apoptosis (i) was prevented by a COX-2 inhibitor and by antagonists of prostaglandin (EP) receptors and (ii) was associated to an increase in intracellular PGE(2) (iPGE(2)) due to hypoxia-inducible factor-1α-dependent transcriptional up-regulation of COX-2. Apoptosis was also prevented by inhibitors of the prostaglandin uptake transporter PGT, which indicated that iPGE(2) contributes to hypoxia-induced apoptosis (on the contrary, hypoxia/reoxygenation-induced PTC death was exclusively due to extracellular PGE(2)). Thus, iPGE(2) is a new actor in the pathogenesis of hypoxia-induced tubular injury and PGT might be a new therapeutic target for the prevention of hypoxia-dependent lesions in renal diseases.