Deregulation of serum-and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure
File(s)
Accepted version
Supporting information
Author(s)
Type
Journal Article
Abstract
Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations1, 2. Analysis of midsecretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival3, 4, 5, 6, is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional importance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling and abolished embryo implantation. By contrast, implantation was unhindered in Sgk1−/− mice, but pregnancy was often complicated by bleeding at the decidual-placental interface and fetal growth retardation and subsequent demise. Compared to wild-type mice, Sgk1−/− mice had gross impairment of pregnancy-dependent induction of genes involved in oxidative stress defenses. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from human subjects with RPL and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.
Date Issued
2011-10-16
Date Acceptance
2011-08-30
Citation
Nature Medicine, 2011, 17, pp.1509-1513
ISSN
1546-170X
Publisher
Nature Publishing Group
Start Page
1509
End Page
1513
Journal / Book Title
Nature Medicine
Volume
17
Copyright Statement
© 2011, Rights Managed by Nature Publishing Group
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
MEDICINE, RESEARCH & EXPERIMENTAL
STROMAL CELLS
PROGESTERONE-RECEPTOR
OXIDATIVE STRESS
EMBRYO IMPLANTATION
DEPENDENT MANNER
MOUSE UTERUS
IN-VITRO
PREGNANCY
EXPRESSION
MICE
Animals
Cell Death
Cells, Cultured
Embryo Implantation
Endometrium
Female
Humans
Immediate-Early Proteins
Infertility, Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidative Stress
Placenta
Pregnancy
Pregnancy Complications
Pregnancy Outcome
Protein-Serine-Threonine Kinases
Stromal Cells
Immunology
11 Medical And Health Sciences
Publication Status
Published