Iron is Responsible for Production of Reactive Oxygen Species Regulating Vasopressin Expression in the Mouse Paraventricular Nucleus

Reactive oxygen species (ROS) act as signaling molecules for maintaining homeostasis, particularly in the regulation of body-fluid balance in the paraventricular nucleus (PVN) of the hypothalamus. However, there has been little discussion regarding the source of ROS generation in this hypothalamic region. Because iron is the most abundant metal in the brain, we hypothesized that iron may act as a source of ROS, which regulate vasopressin (VP) expression. In the present study, we compared the amount of iron in the PVN to that in other forebrain regions of normal ICR mice, and examined the relationship among iron, ROS, and VP in the PVN of the iron-overloaded with iron dextran and iron-chelated mice with deferoxamine. The amount of iron in the PVN was significantly higher than in any of the forebrain regions we examined. The amount of iron in the PVN was significantly increased in iron-overloaded mice, although not in iron-chelated mice. These results suggest that the PVN exhibits high iron affinity. Both ROS production and VP expression in the PVN of iron-overloaded mice were significantly increased relative to levels observed in control mice. VP concentration in blood of iron-overloaded mice was also significantly higher than that of control mice. Interestingly, iron overload did not alter the expression of nitric oxide synthase, another modulator of VP expression. Taken together, our results suggest that high levels of iron in the PVN induce the production of ROS, which regulate VP expression, independent of nitric oxide signaling.