Effects of Placental Ischemia Are Attenuated by 1,25-Dihydroxyvitamin D Treatment and Associated with Reduced Apoptosis and Increased Autophagy

We evaluated the effects of administration of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) during pregnancy on relieving adverse outcomes of preeclampsia and the pathologic and biochemical changes in reduction in uteroplacental perfusion (RUPP) model of rats. On day 1, 7, and 14 of pregnancy, rats in pregnant RUPP plus 1,25(OH)(2)D (RUPP+VD) group (n=15) received 120ng/100g body weight/week of 1,25(OH)(2)D by subcutaneous injection, while rats in normal pregnant (n=12) and the RUPP group (n=14) received 1,25(OH)(2)D vehicle (saline solution). On day 19 of pregnancy, after measure of blood pressure and cardiac function and urine collection, rats were euthanized, and fetal and maternal serum, placenta, and heart and kidney were collected. Fetal mortality, urinary protein, glucose, and parameters for kidney function in serum were measured. We evaluated vitamin D receptor expression and pathological and ultrastructural changes in rat heart, kidney, and placenta. Levels of oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and autophagy were measured in placenta. Compared to RUPP rats, 1,25(OH)(2)D decreased fetal mortality, mean blood pressure, 24-h urinary protein, urine microalbumin, and hyperglycemia in RUPP+VD rats. These were consistent with the improvements of structure impairment in heart, kidney, and placenta of RUPP rat by 1,25(OH)(2)D. In placenta of RUPP rat, the decrease in oxidative stress and ER stress by 1,25(OH)(2)D treatment was accompanied by autophagy activation and apoptosis attenuation. 1,25(OH)(2)D plays a beneficial effect on preeclampsia at the early gestation and might be used as a potential protective agent for preeclampsia. However, the RUPP model only recapitulated the hypoxic origin of preeclampsia; further randomized controlled trial is expected to be performed for validation and evaluation.