Sex differences in renal transcriptome and programmed hypertension in offspring exposed to prenatal dexamethasone

• Prenatal dexamethasone (DEX) induced sex-specific increase in blood pressure in male but not female adult offspring.
• Prenatal DEX elicited renal programming in a sex-specific manner.
• Sex-specific expression of Agt, Agtr1a, and Agtr2a in the renin-angiotensin system were not altered by DEX exposure.
• The resistance of female offspring to prenatal DEX-induced programmed hypertension is related to a lower Agt mRNA expression.
• Glucocorticoid-induced programmed hypertension is sex-specific.

Glucocorticoids, predominantly dexamethasone (DEX), are widely used to reduce the risk of prematurity-related chronic lung disease. However, prenatal DEX treatment links to adverse effects in later life, including hypertension. Given that sex differences exist in the blood pressure (BP) control, and that renal transcriptome is sex-specific, thus we intended to elucidate whether prenatal DEX-induced programmed hypertension is in a sex-specific manner and identify candidate genes and pathways using the whole-genome RNA next-generation sequencing (NGS) approach. Offspring were assigned to 4 groups (n = 7–8/group): male control (MC), female control (FC), male DEX (MD), and female DEX (FD). Dexamethasone (0.1 mg/kg body weight) or vehicle was intraperitoneally administered to pregnant SD rats from gestational day 16–22, to construct a DEX model. Rats were killed at 16 weeks of age. Prenatal DEX induced sex-specific increase in BPs in male but not female adult offspring. Prenatal DEX elicited renal programming in a sex-specific fashion as demonstrated by 8 and 18 DEGs in male and female offspring, respectively. Among them, two genes, Hbb and Hba-a2, were shared. The resistance of female offspring to prenatal DEX-induced programmed hypertension is related to a lower Agt expression. Prenatal DEX induced programmed hypertension in adult male but not female offspring, which was related to renal programming affecting sex-biased genes and the RAS. Early identification of sex-specific underlying mechanisms could provide novel deprogramming strategy to reach maximal optimization in both sexes.