Sexually dimorphic expression of renin-angiotensin system (RAS) may account for differences in cardiovascular and renal disease progression. Perturbations during kidney development can result in reduced nephron endowment and hypertension in offspring in adulthood, with many models showing an effect on renal RAS. In our ovine model of reduced nephron number (due to fetal uninephrectomy at 100 days of gestation, term=150 days) we have shown uni-x male offspring have low plasma renin and reduced renal expression of angiotensin II type 1 and 2 receptors (AT1R and AT2R). This is associated with elevated blood pressure (BP) and reduced renal blood flow (RBF) at 6 months and 4 years of age (1,2).
Aim: The present study determined expression of the renal RAS in male and female fetuses 14 days post- uni-x (114d) and in the adult female. In addition, plasma levels of the RAS were examined in adult female sheep.
Results: Fetal uni-x did not alter renin mRNA levels in the fetus. Fetal uni-x had no effect on AT1R or AT2R expression in female fetuses however both were significantly lower in uni-x male compared to sham counterparts. In adulthood, female uni-x sheep had reduced expression of AT1R, however, AT2R levels were not different between groups. Plasma and tissues levels of renin and angiotensin II were reduced in the uni-x females. In contrast to male sheep, uni-x female sheep had similar BP and RBF to control animals prior to one year of age, however BP was elevated and RBF reduced at 4 years of age.
Conclusion: This study shows the uni-x offspring have reduced circulating renin and angiotensin II associated with sex specific alterations in renal AT receptor expression during both fetal and adult life. An activated RAS is required for appropriate transition of renal function from fetal to extrauterine environment. It is speculated that the onset of renal dysfunction in males may in-part be associated with differential response of RAS to perturbation in kidney development between the sexes incurring an inadequate adaptation of postnatal renal function in males compared to females.