Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Clin Sci (Lond). 2020 Mar 27;134(6):641-656. doi: 10.1042/CS20190765.
Adverse events during fetal life such as insufficient protein intake or elevated transfer of glucocorticoid to the fetus may impact cardiovascular and metabolic health later in adult life and are associated with increased incidence of type 2 diabetes, ischemic heart disease and hypertension. Several adverse factors converge and suppress the fetal renin-angiotensin-aldosterone system (RAAS). The aim of this review is to summarize data on the significance of RAAS for kidney development and adult hypertension. Genetic inactivation of RAAS in rodents at any step from angiotensinogen to angiotensin II (ANGII) type 1 receptor (AT1) receptors or pharmacologic inhibition leads to complex developmental injury to the kidneys that has also been observed in human case reports. Deletion of the 'protective' arm of RAAS, angiotensin converting enzyme (ACE) 2 (ACE-2) and G-protein coupled receptor for Angiotensin 1-7 (Mas) receptor does not reproduce the AT1 phenotype. The changes comprise fewer glomeruli, thinner cortex, dilated tubules, thicker arterioles and arteries, lack of vascular bundles, papillary atrophy, shorter capillary length and volume in cortex and medulla. Altered activity of systemic and local regulators of fetal-perinatal RAAS such as vitamin D and cyclooxygenase (COX)/prostaglandins are associated with similar injuries. ANGII-AT1 interaction drives podocyte and epithelial cell formation of vascular growth factors, notably vascular endothelial growth factor (VEGF) and angiopoietins (Angpts), which support late stages of glomerular and cortical capillary growth and medullary vascular bundle formation and patterning. RAAS-induced injury is associated with lower glomerular filtration rate (GFR), lower renal plasma flow, kidney fibrosis, up-regulation of sodium transporters, impaired sodium excretion and salt-sensitive hypertension. The renal component and salt sensitivity of programmed hypertension may impact dietary counseling and choice of pharmacological intervention to treat hypertension.
胎儿期的不良事件，如蛋白质摄入不足或糖皮质激素向胎儿的转移增加，可能会影响成年后的心血管和代谢健康，并与 2 型糖尿病、缺血性心脏病和高血压的发病率增加有关。有几个不良因素汇聚并抑制胎儿肾素-血管紧张素-醛固酮系统（RAAS）。本综述的目的是总结 RAAS 对肾脏发育和成人高血压的重要性的数据。在血管紧张素原到血管紧张素 II（ANGII） 1 型受体（AT1）受体的任何步骤中，对啮齿动物的 RAAS 进行基因失活或使用药物抑制均可导致肾脏的复杂发育损伤，在人类病例报告中也观察到了这种损伤。删除 RAAS 的“保护”臂，即血管紧张素转换酶（ACE）2（ACE-2）和血管紧张素 1-7（Ang1-7）的 G 蛋白偶联受体（Mas）受体，不会复制 AT1 表型。这些变化包括肾小球数量减少、皮质变薄、肾小管扩张、小动脉和动脉壁增厚、血管束缺失、乳头萎缩、皮质和髓质中毛细血管长度和体积缩短。胎儿围产期 RAAS 的全身和局部调节剂，如维生素 D 和环氧化酶（COX）/前列腺素的活性改变与类似的损伤有关。ANGII-AT1 相互作用驱动足细胞和上皮细胞形成血管生长因子，特别是血管内皮生长因子（VEGF）和血管生成素（Angpts），它们支持肾小球和皮质毛细血管生长以及髓质血管束形成和模式化的后期阶段。RAAS 诱导的损伤与肾小球滤过率（GFR）降低、肾血浆流量降低、肾脏纤维化、钠转运体上调、钠排泄受损和盐敏感性高血压有关。程序化高血压的肾脏成分和盐敏感性可能会影响饮食咨询和选择药物干预来治疗高血压。
