Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.
Hypertens Res. 2022 May;45(5):814-823. doi: 10.1038/s41440-022-00889-1. Epub 2022 Mar 18.
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.
肾髓质是调节肾脏钠排泄的关键部位。然而，其分子机制尚不清楚。环氧化酶 2（COX2）特异性表达于肾髓质，有助于维持体内电解质/水平衡。缺氧诱导因子（HIFs）也已在肾髓质中表达，可能归因于肾髓质的缺氧条件。本研究旨在测试 HIF 激活对肾脏钠处理和肾髓质 COX2 表达的影响。我们的数据表明，脯氨酰羟化酶抑制剂（PHI）FG4592 激活 HIF 增强了高盐饮食挑战下的尿钠排泄。此外，FG4592 上调了肾髓质中 COX2 的表达。体外研究进一步支持了 HIF 可以诱导 COX2 表达的发现，并且这种诱导是通过直接结合 Cox2 基因的启动子区域介导的，从而促进其转录。此外，COX2 抑制剂塞来昔布减弱了 FG4592 的利钠作用。综上所述，这些结果表明，HIF 激活通过上调肾髓质中的 COX2 促进钠排泄，从而维持体内钠平衡。
