Interactions between FKBP52 and PRDX6 during murine pregnancy

FK506 binding protein (FKBP52) is an immunophilin which serves as a Hsp90 cochaperone to influence steroid hormone receptor function. Association of FKBP52 with receptor-chaperone complex increases the binding of receptor-hormone binding. Previous studies showed that Fkbp52-/- mice on CD1 and C57BL6/129 genetic backgrounds have normal ovulation and fertilization but have complete implantation failure. P4 supplementation rescued implantation in CD1 Fkbp52?/? females but not in C57BL6/129 Fkbp52?/? females. Hence P4 supplementation can rescue implantation in CD1 Fkbp52?/? females but not in C57BL6/129 Fkbp52?/? females, CD1 Fkbp52?/? females need higher amount of P4 to maintain pregnancy to full term and expression of Fkbp52 in the placenta without Pgr we hypothesized that FKBP52 should have another function independent of its PR cochaperone activity.As a result of two dimensional difference gel electrophoresis and mass spectrometry, antioxidant protein Peroxiredoxin6 (PRDX6) was found to be the only protein that downregulated in Fkbp52-/- uterus independent of P4-PR signaling. We confirmed specific downregulation of Prdx6 in the uterus by Northern Blotting. In addition we demonstrated that oxidative stress was specific to the uterus via 8-isoprostane assay.Injection of paraquat which is an oxidative stress inducing agent to P4 treated Fkbp52-/- mice that normally have %100 implantation inhibited implantation substantially because these mice became more vulnerable to oxidative stress by paraquat injection. Treatment of these mice with N-acetylcysteine and ?-tocopherol antioxidants in addition to paraquat increased implantation success.We showed physical interaction between FKBP52 and PRDX6 in the decidua via immunoprecipitation.We confirmed our in vivo findings about Fkbp52-/- mice also by in vitro studies performed on mouse embryonic fibroblasts.We showed changes in the uteri of Fkbp52-/- mice compared to wild type mice at ultrastructural level via electron microscopy.Our study showed that in addition to its cochaperone function in PR complex FKBP52 also interacts with PRDX6 to balance oxidant/antioxidant status in the uterus and protects pregnancy.