Naoki Okimoto

Superimposed Preeclampsia in Women with Chronic Kidney Disease

Aim: To evaluate whether pregnant women with chronic kidney disease (CKD) adapt poorly to increases in renal blood flow. This can exacerbate renal function and impair perinatal outcome, as there is a major interplay between CKD and preeclampsia (PE). Methods: We analyzed the outcomes of 90 pregnant women with preexisting CKD. The estimated glomerular filtration rate (eGFR) was measured along with the levels of angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor, which might act in the pathophysiology of PE. Results: In pregnancies with CKD, PE and preterm delivery were increased and the increased blood pressure worsened the perinatal outcomes much more than the increased proteinuria. All pregnancies with severe renal insufficiency were delivered preterm because of impaired renal function. The eGFR was correlated significantly with 24-hour creatinine clearance (r = 0.830). Significant differences in sFlt-1 and placental growth factor levels were found between severe PE without any complications and severe superimposed PE (p < 0.05), and between women with and without declining renal function in superimposed PE (p < 0.01). Conclusion: Pregnancies with CKD have a high risk of obstetrical complications. The eGFR might serve for evaluating renal function during pregnancy. Angiogenic factors might be potential markers for a differential diagnosis between PE and worsening renal function.

RGS2 mediates the anxiolytic effect of oxytocin

The neuropeptide oxytocin (OT) has been shown to exert multiple functions in both males and females, and to play a key role in the regulation of emotionality in the central nervous system (CNS). OT has an anxiolytic effect in the CNS of rodents and humans. However, the molecular mechanisms of this effect are unclear. Here we show that OT induced the expression of regulator of G-protein signaling 2 (RGS2), a regulatory factor for anxiety, in the central amygdala (CeA) of female mice. Bath application of OT increased RGS2 levels in slices of the amygdala of virgin mice. RGS2 levels in the CeA were higher in lactating mice than in virgin mice. In contrast, RGS2 levels in mice that had given birth did not increase when the pups were removed. Acute restraint stress for 4h induced RGS2 expression within the CeA, and local administration of an OT receptor antagonist inhibited this expression. Behavioral experiments revealed that transient restraint stress had an anxiolytic effect in wild-type females, and RGS2 levels in the CeA correlated with the anxiolytic behavior. By contrast, in the OT receptor-deficient mice, restraint stress neither increased RGS2 levels in the CeA nor had an anxiolytic effect. These results suggest that OT displays an anxiolytic effect through the induction of RGS2 expression in the CNS.

Oxytocin mediates the antidepressant effects of mating behavior in male mice

A significant association between plasma oxytocin (OT) levels and depression has been demonstrated. A recent study found that sexual activity and mating with a female induced the release of OT in the central nervous system of male rats. Here we examined the effect of mating behavior on depression-related behavior in wild-type (WT) and OT receptor-deficient (OTR KO) male mice. The WT males showed a reduction in depression-related behavior after mating behavior, but the OTR KO mice did not. Application of an OTR antagonist inhibited mating behavior-induced antidepressant effect in WT males. OT may mediate the antidepressant effects of mating behavior.

Acknowledgment to the Reviewers

The editors greatly appreciate the support of all reviewers whose comments and scientific evaluation of submitted manuscripts are invaluable for ensuring the scientific quality of this journal. In addition to the listed permanent members of the Editorial Board, the following distinguished clinicians and scientists listed below acted as reviewers for Gynecologic and Obstetric Investigation from the beginning of November 2011 to the end of October 2012. The Editors hereby express their sincere gratitude for and their appreciation of the work done as well as the support given to this journal.

P3-o09 Oxytocin mediates mating-induced antidepressant effect in male mice

Oxytocin (OXT) is known as a regulator of depression, anxiety and trust behaviors in central nervous system. Moreover, recent studies have shown that OXT mediates mating-induced anxiolysis in male rats. However, it is unclear whether OXT is involved in the antidepressant effect by mating behavior. In the present study, we examined the effect of mating on depression behaviors in wild-type (WT) and OXT receptor-deficient male mice (OXT-R KO). The depression behaviors were measured by forced swim test. Each animal was examined the duration of immobility during swimming for 6 min. In WT male mice, the duration of immobility was significantly reduced at after termination of the mating behavior. In OXT-R KO mice, in contrast, the duration of immobility were not reduced compared with that before mating behavior. These results suggest that OXT is involved in mating-induced antidepressant effect in male mice.

Regulatory mechanism of anxiety by oxytocin

Although bipolar disorder (BD) is a multifactorial disease, it is infrequently manifested by one of pleiotropic effects of a single gene mutation. Patients with chronic progressive external ophthalmoplegia (CPEO) sometimes have comorbid mood disorders. CPEO is a mitochondrial disease, which is accompanied by mitochondrial DNA (mtDNA) defects caused by mutations in nuclear genes such as POLG (mtDNA polymerase). Mitochondrial dysfunction in BD has also been suggested by magnetic resonance spectroscopy and pharmacological studies. We generated transgenic mice, in which mutant POLG was expressed in a neuronspecific manner. The mice showed forebrain-specific defects of mtDNA and exhibited mood disorder-like phenotypes. These abnormal behaviors were worsened by tricyclic antidepressant and improved by lithium. In addition, we screened mutations in POLG gene in 466 BD patients and 508 controls and identified 21 mutations. Among them, mutations located in functional domains were found more frequently in patients. These results suggest that POLG mutations and consequent mtDNA defects could be one of genetic risk factors for BD.