Accumulation of hypoxia inducible factor-1α (HIF-1α) is commonly an acute and beneficial response to hypoxia, while chronically elevated HIF-1α is associated with multiple disease conditions including preeclampsia (PE), a serious hypertensive disease of pregnancy. However, the molecular basis underlying the persistent elevation of placental HIF-1α in PE and its role in the pathogenesis of PE are poorly understood. Here we report that Hif-1α mRNA and HIF-1± protein were elevated in the placentas of pregnant mice infused with angiotensin II type I receptor agonistic autoantibody (AT1-AA), a pathogenic factor in PE. Knockdown of placental Hif-1α mRNA by specific siRNA significantly attenuated hallmark features of PE induced by AT1-AA in pregnant mice including hypertension, proteinuria, kidney damage, impaired placental vasculature, and elevated maternal circulating soluble fms-like tyrosine kinase-1 (sFlt-1) levels. Next, we discovered that Hif-1α mRNA levels and HIF-1± protein levels were induced in an independent PE model with infusion of the inflammatory cytokine LIGHT (tumor necrosis factor superfamily member 14). SiRNA knockdown experiments also demonstrated that elevated HIF-1α contributed to LIGHT-induced PE features. Translational studies with human placentas showed that AT1-AA or LIGHT is capable of inducing HIF-1α in a hypoxia-independent manner. Moreover, increased HIF-1α was found to be responsible for AT1-AA or LIGHT-induced elevation of Flt-1 gene expression and production of sFlt-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 PE and highlight novel therapeutic possibilities for the disease.
展开▼
