期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：35
页码：15577-15582
DOI：10.1073/pnas.1009324107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Immunophilin FK506-binding protein 52 (FKBP52) is a cochaperone that binds to the progesterone receptor (PR) to optimize progesterone (P4)-PR signaling. We recently showed that Fkbp52-deficient (Fkbp52-/-) mice have reduced uterine PR responsiveness and implantation failure which is rescued by excess P4 supplementation in a genetic background-dependent manner. This finding led us to hypothesize that FKBP52 has functions in addition to optimizing PR activity. Using proteomics analysis, we found that uterine levels of peroxiredoxin-6 (PRDX6), a unique antioxidant, are significantly lower in Fkbp52-/- mice than in WT and PR-null (Pgr-/-) mice. We also found that Fkbp52-/- mice with reduced uterine PRDX6 levels are susceptible to paraquat-induced oxidative stress (OS), leading to implantation failure even with P4 supplementation. The same dose of paraquat did not interfere with implantation in WT mice. Moreover, treatment with antioxidants {alpha}-tocopherol and N-acetylcysteine (NAC) attenuated paraquat-induced implantation failure in P4-treated Fkbp52-/- mice. Functional analyses using mouse embryonic fibroblasts show that Fkbp52 deficiency associated with reduced PRDX6 levels promotes H2O2-induced cell death, which is reversed by the addition of NAC or by forced expression of PRDX6, suggesting that Fkbp52 deficiency diminishes the threshold against OS by reducing PRDX6 levels. These findings provide evidence that heightened uterine OS in Fkbp52-/- females with reduced PRDX6 levels induces implantation failure even in the presence of excess P4. This study shows that FKBP52-PRDX6 signaling protects pregnancy from overt OS.
