title: Renal growth retardation following angiotensin II type 1 (AT₁) receptor antagonism is associated with increased AT₂ receptor protein in fetal sheep.
abstract: The actions of angiotensin II on type 1 (AT₁) and type 2 (AT₂) receptor subtypes are important for normal kidney development before birth. This study investigated the effect of AT₁ receptor antagonism on renal growth and growth regulators in fetal sheep during late gestation. From 125 days of gestation (term 145±2 days), chronically catheterised sheep fetuses were infused intravenously for 5 days with either an AT₁-specific receptor antagonist (GR138950, 2-4 mg/kg per day, n=5) or saline (0.9% NaCl, n=5). Blockade of the AT₁ receptor decreased arterial blood oxygenation and pH and increased blood pCO₂, haemoglobin and lactate, and plasma cortisol and IGF-II. Blood glucose and plasma thyroid hormones and IGF-I were unchanged between the treatment groups. On the 5th day of infusion, the kidneys of the GR-treated fetuses were lighter than those of the control fetuses, both in absolute and relative terms, and were smaller in transverse cross-sectional width and cortical thickness. In the GR-infused fetuses, renal AT₂ receptor protein concentration and glomerular density were significantly greater than in the saline-infused fetuses. Blockade of the AT₁ receptor had no effect on relative cortical thickness, fractional or mean glomerular volumes, or renal protein levels of the AT₁ receptor, IGF type 1 receptor, insulin receptor or protein kinase C ζ. Therefore, in the ovine fetus, AT₁ receptor antagonism causes increased renal protein expression of the AT₂ receptor subtype, which, combined with inhibition of AT₁ receptor activity, may be partly responsible for growth retardation of the developing kidney.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. ajf1005@cam.ac.uk
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Forhead
authors.forename: Juanita K
authors.initials: JK
authors.lastname: Jellyman
authors.forename: Katherine
authors.initials: K
authors.lastname: Gillham
authors.forename: Janelle W
authors.initials: JW
authors.lastname: Ward
authors.forename: Dominique
authors.initials: D
authors.lastname: Blache
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Fowden
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001158:Arteries; D001572:Benzofurans / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation / Q000378:metabolism*; D005333:Fetus / Q000033:anatomy & histology / Q000378:metabolism*; D005865:Gestational Age; D006728:Hormones / Q000097:blood; D007262:Infusions, Intravenous; D007668:Kidney / Q000196:embryology*; D009929:Organ Size / Q000187:drug effects; D009994:Osmolar Concentration; D010100:Oxygen / Q000097:blood; D011506:Proteins / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D012756:Sheep / Q000196:embryology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001572:Benzofurans; D006728:Hormones; D011506:Proteins; D044139:Receptor, Angiotensin, Type 2; D010100:Oxygen; C089586:saprisartan potassium