Impact of diet and stress on the development of preeclampsia-like symptoms in p57^kip2 mice

Abstract

Impact of diet and stress on the development of preeclampsia-like symptoms in p57 kip2 mice. Am J Physiol Heart Circ Physiol 296: H119 -H126, 2009. First published October 31, 2008 doi:10.1152/ajpheart.01011.2008.-The cyclin-dependent kinase inhibitor p57 kip2 regulates the cell cycle of trophoblastic cells. It has been established by a Japanese group that the heterozygous p57 kip2 knockout (p57 Ϫ/ϩ ) mice are a good model of preeclampsia as they develop hypertension, proteinuria, and placental pathology. However, apart from the placental pathology, we could not observe these symptoms in our laboratory. Hence, we investigated the impact of diet and stress on this model. To do so, we compared the effects of the Japanese diet to that of the North American diet used by our animal facility. Furthermore, the impact of stress was determined by placing the mice in a restraining device before and at the end of gestation. Although the Japanese diet did not have any impact on blood pressure or proteinuria, the mice did develop endothelial dysfunction, left ventricular hypertrophy, as well as increased placental pathology. Also, all mice had smaller litters when fed the Japanese diet. However, stress response of these mice was not increased during gestation; in fact, a decrease was observed in the p57 Ϫ/ϩ mice, suggesting that this was probably not a player in the development of the pathology. Taken together, these results suggest that other environmental factors may have been implicated in the development of preeclampsia-like symptoms in this animal model. Moreover, we demonstrated that placental pathology and genetic factors are not sufficient to trigger preeclampsia-like symptoms in this model and that the diet might play an important part in the development of this multifactorial disease. knockout mouse; diet; stress; blood pressure; preeclampsia PREECLAMPSIA (PE) is the most important cause of maternal and perinatal morbidity and mortality (34). It is human pregnancyassociated syndrome diagnosed with a new appearance of hypertension and proteinuria (23), which resolve completely after delivery (31), suggesting that feto-placental factors are the main origin of the pathology. Many studies have demonstrated the significant impact of abnormal placentation in the development of PE,

The potential impact of the fetal genotype on maternal blood pressure during pregnancy

“…Phenotypically wild-type pregnant female mice carrying litters where half of the offspring have targeted disruption of Cdkn1c (also known as p57 kip2 ) genes develop a condition similar to preeclampsia with hypertension and proteinuria, as well as thrombocytopenia, decreased antithrombin III activity, and increased endothelin concentrations during late pregnancy [64]. The environment modulates the risk of these signs developing [65]. Comparable to findings of preeclampsia in mothers carrying fetuses with CDKN1C mutations [41], in these mice, the maternal blood pressure and proteinuria, as well as the other factors, return to normal postpartum [64].…”

p57KIP2: “Kip”ing the Cell under Control

“…The observed trophoblastic hyperplasia may be the leading cause (188). Further studies, failed to recapitulate pre-eclampsia manifestations in the particular mouse model, although they invariably exhibited placenta abnormalities, suggesting the significance of environmental factors in the development of this disease (188,189). Recently, Romanelli and colleagues (190) reported the existence of three women with haemolysis, elevated liver enzymes, and low platelets (HELLP)-preeclampsia who gave birth to children with BWS possessing mutations in p57 KIP2 .…”

Mice Overexpressing Both Human Angiotensinogen and Human Renin as a Model of Superimposed Preeclampsia on Chronic Hypertension

“…Kidneys, hearts, and placentas were all collected, weighed, and either flash frozen in liquid nitrogen or fixed until further assessment, as published previously. 25,26 Placental alterations were characterized by 5 criteria: necrosis, hyalinization, microcalcification, giant cell island loss, and labyrinthine trophoblast structure loss as done previously. 25,26 The latter 2 are, respectively, analogous to human extravillous cytotrophoblasts cells and chorionic villi structure.…”

“…25,26 Proteinuria Urine samples were collected before and on day 18 of gestation, and albumin and creatinine concentrations were quantified as described previously. 25,26 …”

“…25,26 Placental alterations were characterized by 5 criteria: necrosis, hyalinization, microcalcification, giant cell island loss, and labyrinthine trophoblast structure loss as done previously. 25,26 The latter 2 are, respectively, analogous to human extravillous cytotrophoblasts cells and chorionic villi structure. 5 A score from 0 to 3 was assigned for each criterion: 0 for no change, 1 for mild, 2 for moderate, and 3 for severe alteration.…”