Hypoxia-Independent Upregulation of Placental Hypoxia Inducible Factor-1α Gene Expression Contributes to the Pathogenesis of Preeclampsia

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2015-06, Vol.65 (6), p.1307-1315
• Main Authors: Iriyama, Takayuki, Wang, Wei, Parchim, Nicholas F, Song, Anren, Blackwell, Sean C, Sibai, Baha M, Kellems, Rodney E, Xia, Yang
• Format: Article
• Language: English
• Subjects: Animals; Autoantibodies - administration & dosage; Disease Models, Animal; Female; Fetal Hypoxia - physiopathology; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Mice; Placenta - metabolism; Placenta - physiopathology; Pre-Eclampsia - physiopathology; Pre-Eclampsia - therapy; Pregnancy; Pregnancy, Animal; Random Allocation; Receptor, Angiotensin, Type 2 - administration & dosage; RNA, Messenger - analysis; RNA, Small Interfering - analysis; Sensitivity and Specificity; Tumor Necrosis Factor Ligand Superfamily Member 13 - genetics; Tumor Necrosis Factor Ligand Superfamily Member 13 - metabolism; Up-Regulation
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.115.05314

Accumulation of hypoxia inducible factor-1α (HIF-1α) is commonly an acute and beneficial response to hypoxia, whereas chronically elevated HIF-1α is associated with multiple disease conditions, including preeclampsia, a serious hypertensive disease of pregnancy. However, the molecular basis underlying the persistent elevation of placental HIF-1α in preeclampsia and its role in the pathogenesis of preeclampsia are poorly understood. Here we report that Hif-1α mRNA and HIF-1α protein were elevated in the placentas of pregnant mice infused with angiotensin II type I receptor agonistic autoantibody, a pathogenic factor in preeclampsia. Knockdown of placental Hif-1α mRNA by specific siRNA significantly attenuated hallmark features of preeclampsia induced by angiotensin II type I receptor agonistic autoantibody in pregnant mice, including hypertension, proteinuria, kidney damage, impaired placental vasculature, and elevated maternal circulating soluble fms-like tyrosine kinase-1 levels. Next, we discovered that Hif-1α mRNA levels and HIF-1α protein levels were induced in an independent preeclampsia model with infusion of the inflammatory cytokine tumor necrosis factor superfamily member 14 (LIGHT). SiRNA knockdown experiments also demonstrated that elevated HIF-1α contributed to LIGHT-induced preeclampsia features. Translational studies with human placentas showed that angiotensin II type I receptor agonistic autoantibody or LIGHT is capable of inducing HIF-1α in a hypoxia-independent manner. Moreover, increased HIF-1α was found to be responsible for angiotensin II type I receptor agonistic autoantibody or LIGHT-induced elevation of Flt-1 gene expression and production of soluble fms-like tyrosine kinase-1 in human villous explants. Overall, we demonstrated that hypoxia-independent stimulation of HIF-1α gene expression in the placenta is a common pathogenic mechanism promoting disease progression. Our findings reveal new insight to preeclampsia and highlight novel therapeutic possibilities for the disease.