Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
J Endocrinol. 2011 Feb;208(2):137-45. doi: 10.1677/JOE-10-0360. Epub 2010 Nov 22.
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.
血管紧张素 II 对 1 型 (AT₁) 和 2 型 (AT₂) 受体亚型的作用对于出生前正常肾脏发育很重要。本研究探讨了在妊娠晚期胎儿羊中，AT₁ 受体拮抗作用对胎儿肾脏生长和生长调节剂的影响。从妊娠 125 天（足月 145±2 天）开始，对长期置管的胎儿羊进行静脉输注，连续输注 5 天，分别给予 AT₁ 特异性受体拮抗剂（GR138950，每天 2-4mg/kg，n=5）或生理盐水（0.9%NaCl，n=5）。AT₁ 受体阻断可降低动脉血氧分压和 pH 值，增加血 pCO₂、血红蛋白和乳酸，以及血浆皮质醇和 IGF-II。两组治疗之间血糖和血浆甲状腺激素和 IGF-I 无变化。在输注的第 5 天，GR 处理的胎儿肾脏的重量，无论是绝对值还是相对值，均比对照组的胎儿轻，且横截面积和皮质厚度均较小。在 GR 输注的胎儿中，肾脏 AT₂ 受体蛋白浓度和肾小球密度明显高于生理盐水输注的胎儿。AT₁ 受体阻断对相对皮质厚度、肾小球体积分数或平均体积、肾脏 AT₁ 受体、IGF 型 1 受体、胰岛素受体或蛋白激酶 C ζ 蛋白水平无影响。因此，在绵羊胎儿中，AT₁ 受体拮抗作用导致 AT₂ 受体亚型的肾脏蛋白表达增加，这与 AT₁ 受体活性的抑制相结合，可能部分导致发育中肾脏的生长迟缓。
