Abstract
Preeclampsia is a syndrome with diverse clinical presentation that currently has no cure. The apelin receptor system is a pleiotropic pathway with a potential for therapeutic targeting in preeclampsia. We established the systemic outcomes of (Pyr1)-apelin-13 administration in rats with preeclamptic features (TGA-PE, female transgenic for human angiotensinogen mated to male transgenic for human renin). (Pyr1)-apelin-13 (2 mg/kg/day) or saline was infused in TGA-PE rats via osmotic minipumps starting at day 13 of gestation (GD). At GD20, TGA-PE rats had higher blood pressure, proteinuria, lower maternal and pup weights, lower pup number, renal injury, and a larger heart compared to a control group (pregnant Sprague-Dawley rats administered vehicle). (Pyr1)-apelin-13 did not affect maternal or fetal weights in TGA-PE. The administration of (Pyr1)-apelin-13 reduced blood pressure, and normalized heart rate variability and baroreflex sensitivity in TGA-PE rats compared to controls. (Pyr1)-apelin-13 increased ejection fraction in TGA-PE rats. (Pyr1)-apelin-13 normalized proteinuria in association with lower renal cortical collagen deposition, improved renal pathology and lower immunostaining of oxidative stress markers (4-HNE and NOX-4) in TGA-PE. This study demonstrates improved hemodynamic responses and renal injury without fetal toxicity following apelin administration suggesting a role for apelin in the regulation of maternal outcomes in preeclampsia.
Highlights
Maternal Weight, g Pup Weight, g Pup Length, cm Number of Pups Placental Weight, g Fetal/Placental Weight Ratio Pup Resorption, Number Maternal Total Kidney Weight/Body Weight, g Maternal Heart Weight/Body Weight, g Food Intake, g Water Intake, ml Urine Volume, ml Serum Total Apelin Levels, ng/ml
Since heart weight was greater in TGA-PE rats, we explored whether preeclampsia altered systolic function and whether (Pyr1)-apelin-13 had affected ejection fraction, stroke volume, www.nature.com/scientificreports mmHg mmHg
Many advances have been made in the past decade in establishing the mechanisms of preeclampsia; no specific therapies are available for the treatment of this disorder
Summary
Maternal Weight, g Pup Weight, g Pup Length, cm Number of Pups Placental Weight, g Fetal/Placental Weight Ratio Pup Resorption, Number Maternal Total Kidney Weight/Body Weight, g Maternal Heart Weight/Body Weight, g Food Intake, g Water Intake, ml Urine Volume, ml Serum Total Apelin Levels, ng/ml. Since the systemic effects of exogenously administered apelin in preeclampsia are not well described, the goal of this study was to determine the effects of a systemically administrated and more stable form of apelin, (Pyr1)-apelin-13, on maternal and fetal characteristics, and cardiovascular and renal outcomes in an established rat model with preeclamptic features (TGA-PE, female transgenic for human angiotensinogen mated to male transgenic for human renin) This model was chosen based on the following characteristics: lower circulating levels of apelin, the expression of many features of human preeclampsia such as increased blood pressure at late pregnancy, intrauterine growth restriction, proteinuria, increased circulating sFlt and vasopressin, the presence of circulating agonistic antibodies to angiotensin II receptor 1, and glomerular endotheliosis versus Sprague Dawley rats (controls), and good reproducibility[19,20,21]
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