The hypoxia-inducible factor prolyl hydroxylase inhibitor FG4592 promotes natriuresis through upregulation of COX2 in the renal medulla

The renal medulla is a key site for the regulation of renal sodium excretion. However, the molecular mechanism remains unclear. Cyclooxygenase 2 (COX2) is specifically expressed in the renal medulla and contributes to the maintenance of the electrolyte/water balance in the body. Hypoxia-inducible factors (HIFs) have also been found to be expressed in the renal medulla, probably owing to the hypoxic conditions in the renal medulla. This study was designed to test the effects of HIF activation on renal sodium handling and renal medullary COX2 expression. Our data showed that HIF activation by the prolyl hydroxylase inhibitor (PHI) FG4592 enhanced natriuresis in mice challenged with a high-salt diet. In addition, FG4592 upregulated the expression of COX2 in the renal medulla. An in vitro study further supported the finding that HIF can induce the expression of COX2 and that this induction is mediated through direct binding to the promoter region of the Cox2 gene, facilitating its transcription. In addition, the COX2 inhibitor celecoxib diminished the natriuretic effect of FG4592. Together, these results suggest that HIF activation promotes sodium excretion through upregulation of COX2 in the renal medulla and therefore maintains sodium homeostasis in the body.