title: Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure.
abstract: Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations. Analysis of midsecretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival, 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.
authors: Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, UK.
authors: Madhuri S
authors: MS
authors: Salker
authors: Mark
authors: M
authors: Christian
authors: Jennifer H
authors: JH
authors: Steel
authors: Jaya
authors: J
authors: Nautiyal
authors: Stuart
authors: S
authors: Lavery
authors: Geoffrey
authors: G
authors: Trew
authors: Zoe
authors: Z
authors: Webster
authors: Marwa
authors: M
authors: Al-Sabbagh
authors: Goverdhan
authors: G
authors: Puchchakayala
authors: Michael
authors: M
authors: Föller
authors: Christian
authors: C
authors: Landles
authors: Andrew M
authors: AM
authors: Sharkey
authors: Siobhan
authors: S
authors: Quenby
authors: John D
authors: JD
authors: Aplin
authors: Lesley
authors: L
authors: Regan
authors: Florian
authors: F
authors: Lang
authors: Jan J
authors: JJ
authors: Brosens
mesh_terms: D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D010064:Embryo Implantation / Q000502:physiology*; D004717:Endometrium / Q000166:cytology / Q000201:enzymology*; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007247:Infertility, Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D010920:Placenta / Q000166:cytology / Q000502:physiology; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases