Abstract P169: Antenatal Betamethasone Attenuates the Angiotensin-(1-7)/Nitric Oxide Axis in Adult Male but not Female Renal Proximal Tubule Cells

Abstract

Our studies have revealed a sex-specific effect of fetal programming on sodium (Na+) excretion in adult sheep whereby the males exhibit reduced Na+ excretion and an attenuated natriuretic response to Ang-(1-7) as compared to the females. We hypothesize that the renal proximal tubules are a key target for the early programming effects of glucocorticoids exposure to regulate Na+ handling in the adult males. Therefore, we isolated and cultured cortical proximal tubule cells (RPTC) from adult male and female sheep antenatally exposed to betamethasone (Beta) or vehicle. Na+ uptake and nitric oxide (NO) were assessed with Sodium Green and DAF fluorescence prior to and following a low dose of Ang-(1-7) (1x10-11 M) in isolated RPTC from sheep at ~1.5 years of age. Data are expressed as % of basal uptake or area under the curve (AUC) for Na+ or % of control for NO. Male Beta RPTC exhibit greater Na+ uptake than male vehicle cells (427±32%, n=13, vs. 315±28%, n=14, p<0.05; however, Beta had no effect on Na+ uptake in the female cells (242±18%, n=9, vs. 250±15%, n=10, p>0.05). Ang-(1-7) inhibited Na+ uptake in RPTC from vehicle male (255±40%) and from both vehicle (191±14%) and Beta (209±11%) females (Figure 1B), but failed to attenuate Na+ uptake in Beta male cells (Figure 1A). Beta exposure also abolished NO stimulation by Ang-(1-7) in male but not female RPTC (Figure 1C). We conclude that an Ang-(1-7)-NO-dependent pathway contributes to the sex-dependent consequences of programming on Na+ regulation in the proximal tubules of the kidney. Moreover, the RPTC retain both the sex and Beta-induced phenotype of the adult and may reflect an appropriate cell model of fetal programming.