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 (AT 1 ) and type 2 (AT 2 ) receptor subtypes are important for normal kidney development before birth. This study investigated the effect of AT 1 receptor antagonism on renal growth and growth regulators in fetal sheep during late gestation. From 125 days of gestation (term 145G2 days), chronically catheterised sheep fetuses were infused intravenously for 5 days with either an AT 1 -specific receptor antagonist (GR138950, 2-4 mg/kg per day, nZ5) or saline (0 . 9% NaCl, nZ5). Blockade of the AT 1 receptor decreased arterial blood oxygenation and pH and increased blood pCO 2 , 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 AT 2 receptor protein concentration and glomerular density were significantly greater than in the saline-infused fetuses. Blockade of the AT 1 receptor had no effect on relative cortical thickness, fractional or mean glomerular volumes, or renal protein levels of the AT 1 receptor, IGF type 1 receptor, insulin receptor or protein kinase C z. Therefore, in the ovine fetus, AT 1 receptor antagonism causes increased renal protein expression of the AT 2 receptor subtype, which, combined with inhibition of AT 1 receptor activity, may be partly responsible for growth retardation of the developing kidney.

Hypothyroidism in utero stimulates pancreatic beta cell proliferation and hyperinsulinaemia in the ovine fetus during late gestation

“…; Forhead et al . ). Intra‐assay CVs were 4–5%, and minimum levels of detection were 0.09, 0.08 and 4.0 ng ml −1 , respectively.…”

“…Plasma insulin and cortisol concentrations were measured using ELISA kits (insulin: Mercodia, Uppsala, Sweden; cortisol: IBL International, Hamburg, Germany); intra-assay CVs were both 9%, and minimum levels of detection were 0.05 and 2.5 ng ml −1 , respectively. Plasma concentrations of leptin, IGF-I and IGF-II were determined by radioimmunoassay as previously described (Blache et al 2000;Forhead et al 2011). Intra-assay CVs were 4-5%, and minimum levels of detection were 0.09, 0.08 and 4.0 ng ml −1 , respectively.…”

Thyroid Deficiency Before Birth Alters the Adipose Transcriptome to Promote Overgrowth of White Adipose Tissue and Impair Thermogenic Capacity

“…Plasma insulin and cortisol concentrations were determined using enzyme-linked immunosorbent assay (ELISA) kits (insulin: Mercodia, Uppsala, Sweden; cortisol: IBL International, Hamburg, Germany); the intra-assay coefficients of variation were both 9%, and the minimum levels of detection were 0.025 and 2.5 ng/mL, respectively. Plasma concentrations of leptin, like growth factor (IGF)-I, and IGF-II were determined by RIA as previously described (21,22). The intra-assay coefficients of variation were 4-5%, and the minimum levels of detection were 0.09, 0.08, and 4.0 ng/mL, respectively.…”

Maternal high-fat diet programs rat offspring hypertension and activates the adipose renin-angiotensin system

“…43 The RAS is important for normal kidney growth, since fetal AT1 receptor antagonism results in decreased kidney weight in rats 44 and sheep 45 . Moreover, a functioning RAS is required for normal nephrogenesis, since, in rats, perinatal suppression of Ang II or blockade of the AT1 receptor are associated with decreased number of glomeruli, glomerular enlargement and hypertension in adults.…”