Uterine FK506-binding protein 52 (FKBP52)–peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress

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 α-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.

[1]  H. Bradshaw,et al.  Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice. , 2010, The Journal of clinical investigation.

[2]  I. Lambrinoudaki,et al.  The role of the oxidative-stress in the endometriosis-related infertility , 2009, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[3]  Y. Taketani,et al.  Deficiency of immunophilin FKBP52 promotes endometriosis. , 2008, The American journal of pathology.

[4]  J. Blumberg,et al.  Oxidative stress and antioxidants: exposure and impact on female fertility. , 2008, Human reproduction update.

[5]  P. Dennery.  Effects of oxidative stress on embryonic development. , 2007, Birth defects research. Part C, Embryo today : reviews.

[6]  S. Dey,et al.  FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific. , 2007, The Journal of clinical investigation.

[7]  J. Morrow,et al.  Extracellular signal-regulated kinase is a target of cyclooxygenase-1-peroxisome proliferator-activated receptor-delta signaling in epithelial ovarian cancer. , 2007, Cancer research.

[8]  J. Morrow,et al.  Extracellular signal-regulated kinase is a target of cyclooxygenase-1-peroxisome proliferator-activated receptor-delta signaling in epithelial ovarian cancer. , 2007, Cancer research.

[9]  E. Margalioth,et al.  Investigation and treatment of repeated implantation failure following IVF-ET. , 2006, Human reproduction.

[10]  S. Dey,et al.  Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  S. Dey,et al.  Variation in commercial rodent diets induces disparate molecular and physiological changes in the mouse uterus. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  A. Fisher,et al.  Peroxiredoxin 6, a 1-Cys peroxiredoxin, functions in antioxidant defense and lung phospholipid metabolism. , 2005, Free radical biology & medicine.

[13]  Joyce Cheung-Flynn,et al.  Physiological role for the cochaperone FKBP52 in androgen receptor signaling. , 2005, Molecular endocrinology.

[14]  S. Dey,et al.  Proteomic analysis identifies immunophilin FK506 binding protein 4 (FKBP52) as a downstream target of Hoxa10 in the periimplantation mouse uterus. , 2005, Molecular endocrinology.

[15]  M. Soares,et al.  A prolactin family paralog regulates reproductive adaptations to a physiological stressor. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Jeff Reese,et al.  Molecular cues to implantation. , 2004, Endocrine reviews.

[17]  L. Zhong,et al.  Heat-shock Treatment-mediated Increase in Transduction by Recombinant Adeno-associated Virus 2 Vectors Is Independent of the Cellular Heat-shock Protein 90* , 2004, Journal of Biological Chemistry.

[18]  David F. Smith.  Tetratricopeptide repeat cochaperones in steroid receptor complexes , 2004, Cell stress & chaperones.

[19]  K. Forsman-Semb,et al.  Mice with Targeted Mutation of Peroxiredoxin 6 Develop Normally but Are Susceptible to Oxidative Stress* , 2003, Journal of Biological Chemistry.

[20]  A. Agarwal,et al.  Vitamin C and vitamin E supplementation reduce oxidative stress-induced embryo toxicity and improve the blastocyst development rate. , 2002, Fertility and sterility.

[21]  B. Hogan,et al.  Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus. , 2002, Developmental biology.

[22]  J. Hiscott,et al.  Posttranslational regulation of IRF-4 activity by the immunophilin FKBP52. , 2000, Immunity.

[23]  R. Maas,et al.  Hoxa-10 regulates uterine stromal cell responsiveness to progesterone during implantation and decidualization in the mouse. , 1999, Molecular endocrinology.

[24]  J. Morrow,et al.  Mass spectrometric quantification of F2-isoprostanes in biological fluids and tissues as measure of oxidant stress. , 1999, Methods in enzymology.

[25]  S. Phelan.  AOP2 (antioxidant protein 2): structure and function of a unique thiol-specific antioxidant. , 1999, Antioxidants & redox signaling.

[26]  R. Gray,et al.  Alcohol and caffeine consumption and decreased fertility. , 1998, Fertility and sterility.

[27]  S. Dey,et al.  Multiple Female Reproductive Failures in Cyclooxygenase 2–Deficient Mice , 1997, Cell.

[28]  J. Kay.  Structure-function relationships in the FK506-binding protein (FKBP) family of peptidylprolyl cis-trans isomerases. , 1996, The Biochemical journal.

[29]  B. O’Malley,et al.  Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. , 1995, Genes & development.

[30]  M. Klagsbrun,et al.  Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. , 1994, Development.

[31]  B Fischer,et al.  Oxygen tension in the oviduct and uterus of rhesus monkeys, hamsters and rabbits. , 1993, Journal of reproduction and fertility.

[32]  T. Mori,et al.  Protection from oxidative stress by thioredoxin and superoxide dismutase of mouse embryos fertilized in vitro. , 1991, Human Reproduction.

[33]  G. Howe,et al.  Effects of age, cigarette smoking, and other factors on fertility: findings in a large prospective study. , 1985, British medical journal.

[34]  R. Noyes,et al.  Dating the endometrial biopsy. , 1950, American journal of obstetrics and gynecology.