缺氧诱导因子HIF调控肾髓质COX2表达，影响尿钠排泄和系统血压的研究

HIF plays a very important role in the regulation of blood pressure, but the mechanism is not very clear. Our clinical trial of treating anemia with PHI in CKD patients found that PHI could ameliorate hypertension. Several studies identified COX2 was regulated by HIF in tumor cells. Our previous studies revealed that the renal medullary COX2 products may service as homeostatic regulators of sodium balance and blood pressure through paracrine secretion way. Meanwhile, HIF-1α and PHD2 were mainly expressed in the renal medulla. The molecular mechanisms by which renal medullary COX2 expression is regulating by HIF are incompletely defined. The aim of this study is to investigate the role of HIF on the renal medullary COX2 expression and hypertension. The present study will characterize the expression of HIF induction in the kidney of SD rat following high salt diet and examine the role of HIF in mediating this COX2 induction in response to increased dietary salt. This study will provide a new evidence for the pathogensis of hypetension and clinical application of PHI drugs.

缺氧诱导因子（HIF）对高血压具有调控作用，我们近期发现PHI（HIF-α稳定剂）在纠正CKD患者贫血的同时具有降低血压的趋势，更支持HIF/PHI对高血压的调控作用，但其机制尚未明了。有研究指出在肿瘤等病理状态下HIF-1α能够调控COX2。我们前期研究发现肾髓质COX2 产物可以通过旁分泌作用调节肾髓质血流量，维持机体钠平衡和血压稳定。因此我们推测HIF可能通过调控肾髓质COX2而影响系统血压。本研究拟通过（1）高盐饮食干预；(2)高盐饮食联合注射PHI/HIF抑制剂的动物研究；（3）体外培养肾髓质间质细胞，采用基因转染技术上调或下调HIF的表达等方法，探讨HIF/PHI能否通过激活肾髓质COX2的表达，继而调节尿钠排泄，维持系统血压的稳定。本研究有助于深入揭示高血压的发病机制，并为HIF/PHI类药物的临床应用提供新的理论依据。