The circulating, intrauterine and intrarenal renin angiotensin systems in normal and pathological pregnancies

The aim of this thesis is to provide evidence that both the circulating and tissue renin angiotensin systems are crucial for a successful pregnancy outcome, and that dysfunction in these RASs may lead to pathological pregnancy outcomes. Therefore, we have; (1) characterised the circulating RAS in early pregnancy in women who go on to have a normal pregnancy outcome and demonstrated fetal sex specific differences in the maternal circulating RAS; (2) shown that in early pregnancy, the activity of the circulating RAS is different in women who subsequently develop preeclampsia (PreE) or gestational hypertension (GH) before these conditions are diagnosed and that there are also fetal sex specific effects on the maternal RAS; (3) characterised DNA methylation as an epigenetic regulator of the intrauterine RAS (amniotic, decidual and placental RASs) and examined the potential effects of gestational age and labour on the DNA methylation status of these RAS genes; (4) characterised the activity of the circulating and intrarenal RASs in men, non-pregnant women and pregnant Indigenous Australian women (5) as well as in pregnant non-Indigenous Australian women and made the novel observation that the urinary AGT/creatinine ratio may be a very sensitive marker of subclinical renal disease. Furthermore, we have shown that a large proportion of pregnant Indigenous Australian women may have subclinical renal disease; (6) further developed a method for collecting urine samples from neonates, non-toilet trained infants and children so that we can measure the activity of the intrarenal RAS in these individuals. We have assessed how common urinary markers used in assessment of renal health/function are affected by this collection and storage process. These 6 papers characterise the circulating, intrauterine and intrarenal RASs during pregnancy and give evidence that differences in the activities of these RASs may be associated with pathological pregnancies. I have further characterised how the RAS may be either epigenetically regulated or influenced by sex hormones.