Consequent Endotoxemia Relieves Abnormalities in Renal Vasoconstriction and AT1/ACE/ACE2 Signaling in Preeclamptic Offspring: Roles of Sex and Antenatal Ang 1‐7 Therapy

Abstract

The renin angiotensin system plays a pathogenic role in the altered renal homeostasis in inflammatory states such as preeclampsia and endotoxemia. Here, we investigated whether preeclamptic fetal programming modifies hemodynamic and renal vasoconstrictor responsiveness to endotoxemia in adult offspring and whether these interactions are modulated by gestationally administered Ang 1‐7. Preeclampsia was induced by oral administration of L‐NAME (50 mg/kg/day) to pregnant dams. Adult offspring was challenged with lipopolysaccharides (LPS, 5 mg/kg) and changes in blood pressure (BP) and renal vasoconstrictor reactivity were assessed 4 hours later. Contrary to female counterparts, male offspring of PE rats exhibited significant rises in BP that were dramatically reduced after LPS administration. Vasoconstrictions induced by Ang II (0.25‐32 ng), but not phenylephrine (0.41‐900 ng), in isolated perfused kidneys of male and female offspring of PE dams were intensified compared with non‐PE offspring. The heightened Ang II responses were blunted by LPS in male, but not female, preparations. Further, gestational Ang 1‐7 supplementation had no effect on endotoxic hypotension in male offspring, but caused sex‐unrelated attenuation of Ang II and phenylephrine renal vasoconstrictions. Immunohistochemical studies showed that while the renal tubular expression of AT1 receptors and ACE was increased in PE offspring of both sexes, increased ACE2 expression was noted only in female offspring. The upregulation in these molecules was diminished after LPS exposure, an effect that was more apparent in the male gender. Additionally, gestational treatment with Ang1‐7 failed to modify expression patterns of AT1/ACE/ACE2 signaling in PE/LPS offspring. Together, sexual dimorphism exists in the ability of ensuing endotoxic challenge of adult offspring to offset imbalances in renal vasoconstriction and tubular AT1/ACE/ACE2 signaling caused by early PE insult. Further, antenatal Ang 1‐7 therapy rectifies the erupted vasoconstriction anomalies through yet unidentified mechanisms.