Systemic administration of 11β-HSD2 inhibitor results in PE-like features in pregnant rats
Subcutaneous administration of CBX (0.6-2.4mg/kg) from GD7.5 to GD17.5 resulted in a decrease in 11β-HSD2 expression and activity in the placentas (Fig.1A). The significance was achieved in CBX (1.2 and 2.4 mg/kg) groups compared with vehicle group. In contrast, 11β-HSD1 expression level in the placentas was not significantly differed among vehicle and CBX groups (supplemental Fig.S1). As expected, a significant increase in placental corticosterone level was exhibited in CBX (1.2 and 2.4 mg/kg) groups (Fig.1B). Maternal circulatory level of corticosterone was significantly increased from GD 15.5 and reached the peak on GD 19.5 in the rats with CBX (1.2 and 2.4 mg/kg) treatment (Fig.1C).
The pregnant rats with CBX treatment (1.2 and 2.4 mg/kg) displayed PE-like features. As shown in Fig1D, MAP of these rats was significantly elevated from GD 15.5 compared with control rats. They also showed a significant increase in SBP measured on GD 20.5 (Fig.1E). The protein/creatinine in urine was also elevated in the rats with CBX treatment (1.2 and 2.4 mg/kg) (Fig.1F). Histology analysis of kidney showed mesangial hypercellularity and occlusion of capillary loops and the urinary space in the glomeruli (Fig.1G) and a higher histopathological score in CBX groups compared with vehicle group (Fig.1H). IUGR was found in CBX (1.2 and 2.4 mg/kg) groups as evidenced by decreased fetal weight (Fig.1I). Moreover, a significant increase in circulatory sFlt1 level and sFlt1/ PlGF ratio occurred in CBX (1.2 and 2.4 mg/kg) groups (Fig.1J), but circulatory PlGF and VEGF levels were not significantly changed in these animals (supplemental Fig.S2).