Molecular Human Reproduction, Vol. 8, No. 12, 1129-1135,
December 2002
© 2002 European Society of Human Reproduction and Embryology
Molecular aspects of pregnancy |
Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice
1 Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine 3600, Handa-cho, Hamamatsu, Shizuoka 431-3192, 2 Department of Physiological Chemistry, School of Pharmaceutical Sciences, Showa University 1–5–8, Hatanodai, Shinagawa-ku, Tokyo 142-8555 and 3 Laboratory of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University 3-1–1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Abstract
p57Kip2, a potent inhibitor of several cyclin/cyclin dependent kinase complexes (CDK ), is a paternally imprinted gene in both humans and mice, and here we show that pregnant mice which are heterozygous for p57Kip2 deficiency display symptoms similar to preeclampsia. p57–/+ (heterozygotes for p57Kip2 ) female mice that were mated with p57–/+ males showed hypertension, proteinuria, thrombocytopenia, decreased anti-thrombin III activity, and increased endothelin levels during late pregnancy. In their kidneys, endotheliosis of glomeruli were recognized along with fibrinoid or hyalinoid deposits. These characteristics were also observed in pregnant p57–/+ females that were mated with wild type males, but not in pregnant wild type females mated with p57–/+ males or wild type males. The pregnant p57–/+ mice had conceptuses both with and without p57Kip2 expression. The conceptuses without p57Kip2 expression showed trophoblastic hyperplasia, which mimics the hallmark proliferation of intermediate trophoblasts in clinical preeclampsia. It is suggested that the preeclampsia-like symptoms of the pregnant p57–/+ mice might have been induced by the conceptus(es) without p57Kip2 expression. In addition, pregnant p57–/+ mice might serve as a new animal model for preeclampsia characterized by trophoblastic hyperplasia.
cyclin-dependent kinase inhibitor/genome imprinting/preeclampsia/trophoblast
Introduction
Preeclampsia is a placental disorder that links placental hypocirculation and hypoxia (Woods and Brooks 1989
; Zamorski and Green, 1996; Hsueh, 1997; Henriksen, 1998). Placental ischemia accounts for several clinical findings associated with pregnancy-induced hypertension and intrauterine growth retardation (Zhou et al., 1998), and there is cross-talk between placental ischemia and abnormal trophoblast invasion (Sheppard and Bonnar, 1999). Characteristic preeclamptic placentae are large and generally show an excess of immature intermediate trophoblasts. Such pathological features are frequently observed in hydropic placentae, diabetic placentae, twin placentae, and hydatidiform moles, all of which cases are at high risk for preeclampsia. Some preeclamptic placentae not associated with known risk factors are small and show abnormally superficial uterine implantation. The villous trophoblasts in preeclamptic placentae are phenotypically immature intermediate trophoblasts (Redline and Patterson, 1995; Roberts, 2000). Thus, proliferation of intermediate trophoblasts is thought to be an important factor in the aetiology of preeclampsia.
The cell cycle of trophoblastic cells, as well as other cells, is regulated by cyclins and cyclin dependent kinases (CDKs). The CDK inhibitor p57Kip2 has the ability to bind with a variety of cyclin-CDK complexes and to inhibit their kinase activities in vitro (Lee et al., 1995; Matsuoka et al., 1995). The p57Kip2 gene is a paternally imprinted gene, and it is located within a cluster of imprinted genes in humans (chromosome 11p15.5) and mice (distal chromosome 7) (Hatada and Mukai, 1995; Matsuoka et al., 1996; Taniguchi et al., 1997). In humans, loss of the maternally-derived 11p15.5 region is implicated in sporadic tumours and in Beckwith–Wiedemann syndrome (BWS) which is characterized by congenital malformations and organomegaly, and is associated with an increased risk for the development of childhood neoplasms (Engel et al., 2000; Hatada and Mukai, 2000; Maher and Reik, 2000). Abnormal expression of imprinted genes is implicated in the pathogenesis of certain paediatric tumours (Hatada et al., 1996; Lee et al., 1997; O'Keefe et al., 1997; Algar et al., 1999, 2000; Bhuiyan et al., 1999; Lam et al., 1999). p57Kip2 mutations have been found only rarely in association with BWS, but a decrease in p57Kip2 expression levels has been detected in several kinds of tumours (Thompson et al., 1996; Liu et al., 1997; Chilosi et al., 1998; Bourcigaux et al., 2000; Oya and Schulz, 2000; Tsugu et al., 2000).
Mice deficient in the p57Kip2 gene show defective endochondral bone formation. Most of these mice die neonatally, as a result of severe cleft palate (Yan et al., 1997; Zhang et al. 1997; Takahashi et al., 2000a). It has been reported that (Zhang et al., 1997) p57Kip2-deficient neonates display organomegaly and abdominal wall defects, two of the hallmarks of BWS, and no p57Kip2-deficient mouse was found that survived beyond the neonatal period. On the contrary, it has been reported that p57Kip2-deficient mice displayed no features of BWS, and a 10% survival rate was observed (Yan et al., 1997; Takahashi and Nakayama, 2000). The reports of surviving mutant mice did not indicate that p57Kip2-deficient mice had tumourous tissues (Yan et al. 1997; Takahashi et al., 2000a).
There are recent indications that a decrease or a loss of p57Kip2 expression is associated with abnormal trophoblastic proliferation (Takahashi et al., 2000b). That is, p57Kip2 expression has also been shown to be reduced markedly in women with malignant trophoblastic neoplasms that cause spontaneous abortion and preterm delivery (Chilosi et al., 1998). Furthermore, in placentae of mouse embryos lacking p57Kip2 expression, hyperplasia involving both labyrinthine trophoblasts and spongiotrophoblasts has been recognized (Takahashi et al., 2000b). The spongiotrophoblasts in mice are thought to be analogous to the intermediate or cell column in humans.
The aim of this study is to determine whether excessive trophoblastic proliferation could induce preeclampsia-like symptoms. We show here that pregnant heterozygous mice for p57Kip2-deficiency develop preeclampsia-like symptoms, i.e., hypertension, proteinuria, thrombocytopenia, and decreased anti-thrombin III (ATIII) activity during late pregnancy. About 50% of the conceptuses of the pregnant p57–/+ mice lacked p57Kip2 expression. It is suggested that these preeclampsia-like symptoms in pregnant p57–/+ females might result from trophoblastic hyperplasia.
Materials and methods
Mice
p57Kip2 knockout (KO) mice used in this study have been previously studied (Takahashi et al., 2000a). In this study, we used the C57BL/6 mice as the parent strain for the p57Kip2 heterozygous mice. We put pairs of mice together in four different mating patterns to obtain conceptuses of four different genotypes (Table I) as determined by PCR of tail DNA. Among the genotypes, wild type (WT) and p57–/+ express the p57Kip2 gene, but p57+*/– and p57–/– do not, as the paternal allele (marked as +*) is imprinted (see Table I). When the genotype of the pregnant females was p57–/+, 50% of the conceptuses would be expected to have p57Kip2 expression and the remainder would lack p57Kip2 expression, independent of the genotype of the males. Heterozygous females were mated with heterozygous males (group I, n = 6 females), or with WT males (group II, n = 6 females), while WT females were mated with heterozygous males (group III, n = 6 females) or with WT males (group IV, n = 6 females). The paired mice were placed together overnight in a cage and prag-positive females were taken out the next morning, 0.5 days postcoitus (dpc).
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All investigations were conducted according to the principles of the Declaration of Helsinki. Our study was also approved by the Animal Research Committee of Hamamatsu University.
Measurement of blood pressure and proteinuria
Blood pressure was measured with a tail-cuff, sensor and dynograph after the behaviour and heart rate of the mice had stabilized (Pfeffer et al., 1971). Blood pressure values were reported as the mean of at least three measurements varying by <5% obtained in one session. Most blood pressure readings fell within a 5% range. For measurements of urinary protein levels, mice were placed from 16.00 h to 20.00 h in metabolic cages with a stainless wire mesh floor. Urine was collected automatically into a plastic container and stored during the collection period. Urolab paper (Sankyo, Tokyo) was used to measure urinary protein and can detect proteinuria between 10 and 3000 mg/dl.
Determination of platelet counts and plasma anti-thrombin III activity, and endothelin-1 concentration
Thrombus formation and activation of coagulation are frequently seen in human preeclampsia (Battistini and Dussault, 1998; Taylor et al., 1998; Kobayashi et al., 1999; Walker, 2000). We therefore investigated the number of platelets, anti-thrombin II (AT III) activity, and endothelin levels in the circulation as the biochemical parameters for confirming preeclampsia in pregnant p57–/+ females. Blood samples were taken from the heart at the time that the mice were killed. Samples of 500 µl were drawn into EDTA-containing tubes for platelet counting. Plasma from the 500 µl sample was drawn into sodium citrate-containing tubes and centrifuged, and the supernatant was collected for measurement of AT III activity by the synthetic substrate S2238 (Daiichikagaku, Tokyo, Japan). The plasma endothelin-1 was measured with an EIA kit for endothelin (Takeda, Osaka, Japan). The intra- and inter-assay coefficients of variation were <10%.
Histological analysis of the kidney
The pregnant mice were killed on day 17.5, and the whole kidney was fixed in 10% formaldehyde. Fixed samples were dehydrated in ascending concentrations of ethanol, cleared in xylene and embedded in paraffin. Sections (5 mm) of the embedded samples were stained by the periodic acid–methanamine-silver (PAM) method for detection of fibrin deposition (Khatun et al., 1999). Sections were viewed with an Olympus AH3 microscope.
Statistical analysis
The data are shown as mean ± SD. The Mann–Whitney U-test was used for significance in proteinuria, platelet counts, AT III activity and endothelin-1 levels. Mean arterial pressure data were analysed by two-way analysis of variance. A P-value of 0.05 was considered statistically significant.
Results
Because p57Kip2 is a paternally imprinted gene that is expressed from the maternally-derived region, the neonates from matings between heterozygotes (group I) are WT, homozygotes (p57–/–), heterozygotes (p57–/+) expressing p57Kip2, and heterozygotes (p57+*/–) not expressing p57Kip2. Neonates from the matings between WT males and p57–/+ females (group II) are WT and p57+*/–, with p57+*/– displaying the phenotype of p57–/–. The genotypes as determined by PCR were WT 15/63, p57–/+ 16/63, p57+/– 16/63, p57–/– 16/63 in group I, WT 32/64, p57+/– 32/64 in group II, WT 30/61, p57–/+ 31/61 in group III, and WT 63/63 in group IV (Table I
). An example of placental histology for each fetal genotype is shown in Figure 1. Homozygotes (p57–/–) and heterozygotes (p57+*/–) without p57Kip2 expression showed a marked increase in proliferation of spongio- and labyrinthine trophoblasts resulting in a narrow labyrinthine space (Figure 1a). The placental weight for conceptuses without p57Kip2 expression on day 17.5 was 140 ± 20 mg and that for conceptuses with p57Kip2 expression was 110 ± 15 mg. The invasion of giant cells tended to be reduced in the p57Kip2 deficient mice in comparison with WT mice (Figure 1b).
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The systolic blood pressure of pregnant female mice in groups I and II began to increase on 9.5 dpc, and it increased continuously until 17.5 dpc, the day of delivery. Two days after delivery, the blood pressure had returned to the levels observed during early pregnancy in groups I and II (Figure 2
). In early pregnancy, there was no statistical difference in systolic blood pressure between the mating groups. Blood pressure of the pregnant mice in groups III and IV remained constant during pregnancy.
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Urinary protein excretion increased remarkably and continuously until the day of delivery in groups I and II. Urinary protein excretion did not differ significantly between the groups at 1.5 dpc. Urinary protein excretion amounted to 0.8 ± 0.4 (mg/day/10 g of body weight) in group I and 0.6 ± 0.4 (mg/day/10 g of body weight) in group IV at 1.5 dpc. The levels were slightly increased in both groups III and IV during pregnancy. Although protein secretion was 2.2 ± 1.9 in group IV at 17.5 dpc, in group I it was 10.9 ± 1.7, five times greater than that of group IV. In this study, the protein excretion level of group II was 2.8 times greater than that of group IV on day 17.5 dpc. After delivery, the levels of protein excretion in groups I and II returned to the state observed during early pregnancy: 2.7 ± 1.0 and 2.0 ± 1.3, respectively (Figure 3
).
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On 17.5 dpc, platelet counts in group I and II females were significantly lower than platelet counts in group III and IV females; counts in group I and group II were 48 and 55% respectively, of the counts in group IV (Figure 4a
). ATIII activity was significantly lower in groups I and II than in groups III and IV; activity in groups I and II was 56 and 59% respectively, of the activity in group IV (Figure 4b). The mean endothelin level in group I on 17.5 dpc was 3.0 times greater than that in group III and IV, and that in group II was 3.5 times greater (Figure 4c).
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PAM staining showed diffusely enlarged glomeruli at 17.5 dpc in kidneys of pregnant mice from groups I and II. An increase in subendothelial and mesangial deposits in the glomerular capillaries shown by brownish staining was also found in these groups (Figure 5
). Furthermore, the shapes of the glomeruli were irregular. In contrast, the glomerular capillaries of the WT kidneys showed only weak pinkish staining, and the gomeruli were circular in shape. Some of the mice of groups I and II had severe glomerular capillary endotheliosis resulting in nephrosclerosis. Moreover, marked fibrinoid or hyaline deposits were detected in proximal and distal tubules in groups I and II. These pathological changes were not observed in groups III and IV. These changes were not seen in non-pregnant p57Kip2 deficient mice (data not shown).
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Discussion
Pregnant p57Kip2–/+ mice in our study showed preeclampsia-like symptoms including hypertension, proteinuria, thrombocytopenia, a decreased anti-thrombin III activity, and increased endothelin levels during late pregnancy. As reported previously, the p57Kip2 gene is imprinted and p57Kip2 is expressed from the maternally-derived allele (Hatada and Mukai, 1995; Matsuoka et al., 1996; Taniguchi et al., 1997). A previous in-situ hybridization study revealed that p57Kip2 mRNA was detected in both WT and p57–/+ mice but not in either p57+*/– or p57–/– mice (Takahashi et al., 2000b). Moreover the placentae without p57Kip2 expression displayed placentomegaly and excess proliferation of trophoblasts (Takahashi et al., 2000b). The p57Kip2 gene has several domains including a proline-rich domain. The mice used in this study lack the whole of p57Kip2 gene, while the other p57Kip2 deficient mice lack only the CDK inhibitor domain. Other p57Kip2 deficient mice have not shown placentomegaly, indicating that the CDK inhibitor part of the p57Kip2 gene may not regulate trophoblastic proliferation (Yan et al., 1997; Zhang et al., 1997).
The proliferation of intermediate trophoblasts possibly causes narrowing of the intervillous space. This study was not designed to elucidate whether trophoblastic hyperplasia is linked to shallow invasion of giant cells. However, smaller numbers of giant cells were seen around maternal vessels in p57Kip2 deficient mice compared to WT mice (Figure 1b). Narrowing of the intervillous space, due to trophoblastic hyperplasia, would impair blood flow from decidua to the spongiotrophoblast and labyrinthine layers, and eventual thrombus formation could occur. Thus, coagulation systems could be activated and endothelial injuries could occur, resulting in the production of vasospastic mediators from the maternal–fetal interface (Battistini and Dussault 1998; Taylor et al., 1998; Kobayashi et al., 1999; Walker, 2000). In the present study, the pregnant p57–/+ mice showed thrombocytopenia and a decrease in ATIII activity reflecting thrombus formation and activation of the coagulatory system.
Endothelin levels in our pregnant p57–/+ mice were significantly higher than levels in pregnant WT mice. Clinically increased levels of endothelin are related to hypertension in cases of preeclampsia. Endothelin is a vasospastic mediator that can be released upon endothelial injury (Battistini and Dussault, 1998; Taylor et al., 1998). Diffuse endothelial injury might occur with diffuse thrombus formation in pregnant p57–/+ mice. Such endothelial injuries could induce hypertension and dysfunction of the kidneys (Kobayashi et al., 1999). Moreover, the fibrin deposition that we observed in the endothelial region of the glomerulus is also a feature of human preeclampsia. A related decrease in renal blood flow could induce or exaggerate the preeclamptic state. It has been reported that overexpression of neuropeptide Y from trophoblasts can induce preeclampsia (Egerman et al., 1999; Khatun et al., 2000). Neuropeptide Y is also a potent vasoconstrictor. Increased neuropeptide Y levels have been seen in p57Kip2 deficient (our unpublished data). Abnormal expression of vasoactive neuropeptides such as neuropeptide Y may be present in the trophoblasts without p57Kip2 expression.
Placentomegaly is considered one of the clinical hallmarks of BWS (Shapiro et al., 1982; Takayama et al., 1986; McCowan and Becroft, 1994). BWS patients with loss of the maternally-derived chromosome 11p15.5, which contains a cluster of imprinted genes including p57Kip2, show abnormal trophoblastic proliferation which is frequently associated with preeclampsia (McCowan and Becroft, 1994). p57Kip2 expression is reported to be low in the hydatidiform mole, which is also frequently associated with a relatively high incidence of severe early-onset preeclampsia (Chilosi et al., 1998). Hyperproliferation of intermediate trophoblasts is recognized in human preeclampsia (Redline and Patterson, 1995). Thus, preeclampsia-like symptoms might be induced by the trophoblastic proliferation that results from the loss of p57Kip2 expression. Clinical findings in both mice and humans also suggest that p57Kip2 plays a central role in inhibition of trophoblastic proliferation. There is at least one other clinical entity, Ballantyne syndrome, that is marked by preeclampsa-like hyperproliferation of trophoblasts (Carbillon et al., 1997; Gherman et al., 1998). Clinical symptoms show hypertension, proteiuria, oedema and hydrops fetalis. Although the pathophysiological mechanisms are unclear, a link to p57Kip2 could be revealed for this condition.
Among the imprinted genes in chromosome p15.5 there are candidates that are implicated in BWS (Engel et al., 2000; Hatada and Mukai, 2000; Maher and Reik, 2000). We have tested the expression levels of both Igf2 and H19 in the placentae of p57 deficient embryos, but there were no differences based on genotypes (Takahashi et al., 2000b). However, the effects of other gene products on the pathogenesis of preeclampsia cannot be ruled out.
In summary, pregnant p57–/+ mice mimic symptoms of human preeclampsia due to the hyperplasia of trophoblasts resulting from the loss of p57Kip2 expression. The onset time of hypertension and proteinuria of pregnant p57–/+ females mice was different from that of human preeclampsia. However, from the standpoint of trophoplastic hyperplasia, an animal model for one type of preeclampsia is suggested.
Acknowledgements
We thank K.Nakayama for his kindness in providing p57Kip2 deficient mice. We also thank S.Khatun, H.M.Belayet and J.Goto for their technical assistance.
Notes
* These authors contributed equally to this work. 
4 To whom correspondence should be addressed. E-mail: kanayama{at}hama-med.ac.jp
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Submitted on June 11, 2002; accepted on September 11, 2002.
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