title: FXR expression is associated with dysregulated glucose and lipid levels in the offspring kidney induced by maternal obesity.
abstract: BACKGROUND
  Maternal obesity is associated with dysregulation of glucose and lipid metabolism with consequent exposure of the fetus to an abnormal metabolic milieu. It is recognized that maternal obesity predisposes offspring to chronic kidney disease (CKD). We aimed to determine whether the nuclear Farnesoid X receptor (FXR), known to play a role in maintaining homeostasis of glucose and lipid metabolism, is involved in renal injury in offspring of obese mothers.
  
  
  METHODS
  Maternal obesity was established in a rat model by feeding dams with high-fat diet prior to and during pregnancy and lactation. The offspring's kidneys were examined at postnatal Day 1and Day 20. Human kidney 2 (HK2) cells were exposed to high glucose with or without the FXR agonist GW4064 or when FXR mRNA was silenced.
  
  
  RESULTS
  Glucose intolerance in the offspring of obese mothers was evident at weaning, with associated downregulation of renal FXR expression and upregulation of monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-β1 (TGF-β1). HK2 cells exposed to high glucose had reduced FXR expression and increased MCP-1, TGF-β1, fibronectin and collagen IV expression, which was reversed in the presence of GW4064. FXR-silenced HK2 cells had amplified pro-inflammatory and pro-fibrotic markers under high glucose conditions.
  
  
  CONCLUSIONS
  Maternal obesity influences renal expression of pro-inflammatory and fibrotic factors that predispose the offspring to CKD. This was associated with the downregulation of the renal FXR expression suggesting a potential protective role for FXR.
authors.affiliation: Kolling Institute, Department of Medicine, University of Sydney, Sydney, Australia ; Department of Endocrinology, Diabetes and Metabolism, Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Glastras
authors.affiliation: Kolling Institute, Department of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Muh Geot
authors.initials: MG
authors.lastname: Wong
authors.affiliation: School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Kolling Institute, Department of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Kolling Institute, Department of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Amgad
authors.initials: A
authors.lastname: Zaky
authors.affiliation: Kolling Institute, Department of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Pollock
authors.affiliation: Kolling Institute, Department of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Saad
keywords: Chronic kidney disease; Developmental programming; Farnesoid X receptor; Maternal obesity; Nuclear hormone receptor; Renal injury