Prenatal hypoxia leads to hypertension, renal renin-angiotensin system activation and exacerbates salt-induced pathology in a sex-specific manner

Abstract

Prenatal hypoxia is associated with growth restriction and adverse cardiovascular outcomes. Here, we describe renal and cardiovascular outcomes in ageing mouse offspring prenatally exposed to hypoxia (12% O2) from embryonic day 14.5 until birth. At 12 months of age, both male and female offspring exposed to prenatal hypoxia had elevated mean arterial pressure. Glomerular number was reduced by 25% in hypoxia-exposed male, but not female, offspring and this was associated with increased urinary albumin excretion, glomerular hypertrophy and renal fibrosis. Hypoxia-exposed offspring of both sexes were more susceptible to salt-induced cardiac fibrosis, however, renal fibrosis was exacerbated by high salt in males only. In male but not female hypoxia-exposed offspring, renal renin mRNA was increased at weaning. By 12 months, renal renin mRNA expression and concentrations were elevated in both sexes. mRNA expression of At 1a R was also elevated in male hypoxia-exposed offspring at 12 months. These results demonstrate that prenatal hypoxia programs elevated blood pressure and exacerbates salt-induced cardiovascular and renal pathology in a sex specific manner. Given sex differences observed in RAS expression and nephron number, future studies may consider RAS blockade as a therapeutic target in this model.

Uteroplacental insufficiency temporally exacerbates salt‐induced hypertension associated with a reduced natriuretic response in male rat offspring

“…; Walton et al . ), although this has not been observed in our model (Wlodek et al . ) and therefore probably does not contribute to enhanced salt‐sensitivity seen in this study.…”

“…In sections stained with Masson's trichrome, perivascular fibrosis and interstitial fibrosis were assessed (Walton et al . ). For perivascular fibrosis, nine arterioles per animal were randomly selected from three separate, non‐sequential slides, and the area of adventitial collagen was normalized to vessel lumen area and averaged for each animal.…”

Prolonged prenatal hypoxia selectively disrupts collecting duct patterning and postnatal function in male mouse offspring

“…Pregnant CD1 mice were either housed under normoxic room conditions ( n = 31; 21% oxygen) or in a hypoxia chamber ( n = 33; 12% oxygen) from E14.5 until birth (P0) as described previously (Cuffe et al . 2014a; Walton et al . 2017).…”

Prenatal hypoxia increases susceptibility to kidney injury

“…The present study does have limitations and raises a number of questions. It has been previously proposed that age and sex play a role in hypertension pathology after prenatal hypoxia [2]. For this reason, it will be important to evaluate the role of age and sex in susceptibility to cisplatin injury of the offspring after prenatal hypoxia.…”

“…Intrauterine hypoxia leading to prenatal hypoxia of the fetus is a common gestational stressor that can lead to a range of developmental abnormalities [1][2][3][4]. When prenatal hypoxia occurs, the developing fetus exhibits a preferential redirection of blood flow, including oxygen and nutrient supply, to the brain and heart over less vital organs such as the kidney [5,6].…”