title: Ovine uterine space restriction causes dysregulation of the renin-angiotensin system in fetal kidneys.
abstract: In ovine pregnancy, uterine space restriction (USR) resulting from decreased space for placental attachment caused intrauterine growth restriction and impaired nephrogenesis. The fetal kidney renin-angiotensin system (RAS) is involved in nephrogenesis, fluid balance, and iron deposition. Angiotensin II exerts its effects via multiple receptors: angiotensin II 1-8 receptor type 1 (AT 1 R) and type 2 (AT 2 R), and angiotensin II 1-7 Mas receptor (MASR).
  
  
  
  : To test the hypothesis that ovine USR is associated with dysregulation of the fetal renal RAS.
  
  
  
  : Multiparous pregnant ewes (n = 32), 16 with surgical bifurcated disconnection of one uterine horn to further reduce placental attachment sites, were studied. USR (n = 31) ovine fetuses were compared to nonspace restricted (NSR) singleton controls (n = 22) on gestational day (GD) 120 or GD130, term GD147. Fetal plasma was collected to evaluate plasma renin activity and iron indices. Fetal kidney AT 1 R, AT 2 R, and MASR proteins were assessed by Western immunoblotting and immunohistochemistry.
  
  
  
  : AT 1 R, AT 2 R, and MASR protein expression was higher in USR at GD130 than aged-matched NSR and USR at GD120, ( P < 0.05 all). AT 1 R and AT 2 R localization was homogenous throughout proximal and distal tubules in both USR and NSR at both gestational dates. MASR localization was punctate throughout renal cortical structures including tubules and glomeruli in both USR and NSR, shifted to intranuclear at GD130. Plasma renin activity was inversely related to plasma osmolarity ( P < 0.02) and was downregulated in USR at GD130 ( P < 0.05).
  
  
  
  : By late gestation, USR upregulated renal angiotensin receptor expression, an effect with potential functional implications.
authors.affiliation: Department of Pediatrics, University of Wisconsin-Madison, Wisconsin, USA.|Department of Nutritional Science, The University of Arizona, Arizona, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Kranch-Shorthouse
authors.affiliation: Department of Pediatrics, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Bauer
authors.affiliation: Department of Pediatrics, University of Wisconsin-Madison, Wisconsin, USA.|Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Wisconsin, USA.|Department of Animal Sciences, University of Wisconsin-Madison, Wisconsin, USA.|Department of Obstetrics and Gynecology, University of South Florida, Florida, USA.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Magness
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Gladys E
authors.initials: GE
authors.lastname: Lopez
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Segar
authors.affiliation: Department of Pediatrics, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Blohowiak
authors.affiliation: Department of Pediatrics, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kling
mesh_terms: D000818:Animals; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism*; D009994:Osmolar Concentration; D011247:Pregnancy; D011945:Receptors, Angiotensin / Q000378:metabolism*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System; D012756:Sheep
chemical_list: D011945:Receptors, Angiotensin; D003404:Creatinine; D007501:Iron; D012083:Renin
keywords: IUGR; RAS; developmental programming; renal development