Pregnant alpha-1-microglobulin (A1M) knockout mice exhibit features of kidney and placental damage, hemodynamic changes and intrauterine growth restriction

Abstract

AbstractAlpha-1-microglobulin (A1M) is an antioxidant previously shown to be elevated in maternal blood during pregnancies complicated by preeclampsia and suggested to be important in the endogenous defense against oxidative stress. A knockout mouse model of A1M (A1Mko) was used in the present study to assess the importance of A1M during pregnancy in relation to the kidney, heart and placenta function. Systolic blood pressure (SBP) and heart rate (HR) were determined before and throughout gestation. The morphology of the organs was assessed by both light and electron microscopy. Gene expression profiles relating to vascular tone and oxidative stress were analyzed using RT-qPCR with validation of selected gene expression relating to vascular tone and oxidative stress response. Pregnant age-matched wild type mice were used as controls. In the A1Mko mice there was a significantly higher SBP before pregnancy that during pregnancy was significantly reduced compared to the control. In addition, the HR was higher both before and during pregnancy compared to the controls. Renal morphological abnormalities were more frequent in the A1Mko mice, and the gene expression profiles in the kidney and the heart showed downregulation of transcripts associated with vasodilation. Simultaneously, an upregulation of vasoconstrictors, blood pressure regulators, and genes for osmotic stress response, ion transport and reactive oxygen species (ROS) metabolism occurred. Fetal weight was lower in the A1Mko mice at E17.5. The vessels in the labyrinth zone of the placentas and the endoplasmic reticulum in the spongiotrophoblasts were collapsed. The gene profiles in the placenta showed downregulation of antioxidants, ROS metabolism and oxidative stress response genes. In conclusion, intact A1M expression is necessary for the maintenance of normal kidney, heart as well as placental structure and function for a normal pregnancy adaptation.