Endocrine Abstracts (2003) 5 OC5

Angiotensinogen; the key to programming female hypertension?

D O'Regan, CJ Kenyon, JR Seckl & MC Holmes


Molecular Endocrinology, School of Molecular and Clinical Medicine, The University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, Scotland, UK.


Adverse events in utero permanently alter the structure and physiology of adult offspring, a phenomenon termed 'foetal programming'. In particular, low birth-weight is associated with an increased risk of adulthood hypertension. Glucocorticoid (GC) administration during pregnancy reduces offspring birth-weight and GCs directly elevate blood pressure (BP) in both humans and rodents. Circulating and local renin-angiotensin-aldosterone (RAAS) system(s) may be involved in programmable hypertension, since all components are present from early gestation and are up regulated by GCs.
The programming effects of prenatal exposure to the synthetic GC, Dexamethasone (Dex), on angiotensinogen (Aogen) mRNA expression and adult offspring BP were investigated in this study.
Female Wistar rats received Dex (100micrograms per Kg per day) or Vehicle (4% ethanol-0.9% saline) injections during the last week of gestation. BP was measured by Tail-Cuff Plethysmography. Aogen mRNA was quantified by Northern blot; results are ratios of Aogen:U1 mRNA (arbitrary units;AU). Oestrous cycle was synchronised in females. Data are mean±SEM; N=6-12/group.
Dex treatment resulted in reduced birth-weight (5.74plus/minus0.05g versus 6.01plus/minus0.05g; n=182; p<0.01) and elevation in 4-month basal corticosterone levels (363.25plus/minus93nMol per litre versus 82plus/minus26nMol per litre; p<0.05). At 5 months, female Dex offspring had higher systolic BP than controls (147plus/minus2.5mmHg versus 132plus/minus2.5mmHg; p<0.01). No differences were found in male Dex offspring. Both groups and sexes had similar plasma renin and aldosterone levels. However, female Dex offspring had increased hepatic Aogen (9.51plus/minus0.27AU versus 8.75plus/minus0.19AU;p<0.05), whilst the males showed a decrease (1.18plus/minus0.05AU versus 1.44plus/minus0.07AU; p<0.05).
Thus, in prenatal Dexamethasone treated females, there is a positive association between increases in hepatic Angiotensinogen mRNA expression and systolic BP. This relationship is not apparent in male offspring. We suggest that sex specific changes in hepatic Angiotensinogen underlie the hypertension associated with prenatal glucocorticoid treatment, and that females are more susceptible to these influences of steroid programming.

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