|Year : 2019 | Volume
| Issue : 1 | Page : 36-41
Lin28B expression in reduced uterine perfusion pressure rat model
Yun Yang, Jia-Po Li, Yue Bian, Gui-Yu Song, Yuan-Yuan Li, Dong-Ying Zheng, Ling Huang, Chong Qiao
Department of Obstetrics and Gynecology, Shengjing Hospital; Key Laboratory of Maternal-Fetal Medicine; Key Laboratory of Obstetrics and Gynecology of Higher Education, China Medical University, Shenyang 110004, Liaoning, China
|Date of Submission||09-Mar-2019|
|Date of Web Publication||11-Apr-2019|
Department of Obstetrics and Gynecology, Shengjing Hospital, China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang 110004, Liaoning
Source of Support: None, Conflict of Interest: None
Objective: Preeclampsia (PE) is a serious complication of pregnancy. Placental ischemia could be an initiating event, but the molecular mechanisms underlying PE are unclear. Lin28B, a paralog of Lin28 RNA-binding protein, is predominantly expressed in human placenta, and decreased Lin28B expression may play a role in PE by reducing trophoblast invasion. The current study was intended to verify whether Lin28B plays a role in the pathogenesis of PE in rat model for reduced uterine perfusion pressure (RUPP).
Methods: We used RUPP rat model. The changes in blood pressure, 24-h urine protein excretion, and fetal development in RUPP rats were recorded and compared to those of normal pregnant (NP) rats. Furthermore, the expression of Lin28B mRNA and protein in placenta was determined using quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry.
Results: The blood pressure, 24-h urine protein excretion, and embryo absorption rate were significantly increased in RUPP rats on the 20th day of gestational period compared with the NP rats (P < 0.001). However, there was no difference in the weight of placenta in RUPP versus NP rats (P > 0.05). The expression levels of Lin28B mRNA and protein in the placenta of RUPP rats were also significantly decreased in comparison to NP rats (P < 0.001).
Conclusion: Our results show that the expression of Lin28B in the placenta of RUPP rats is different from that in NP rats, thus suggesting a role of Lin28B in the pathogenesis of preeclampsia.
Keywords: Lin28B; Placenta; Preeclampsia; Reduced Uterine Perfusion Pressure
|How to cite this article:|
Yang Y, Li JP, Bian Y, Song GY, Li YY, Zheng DY, Huang L, Qiao C. Lin28B expression in reduced uterine perfusion pressure rat model. Reprod Dev Med 2019;3:36-41
|How to cite this URL:|
Yang Y, Li JP, Bian Y, Song GY, Li YY, Zheng DY, Huang L, Qiao C. Lin28B expression in reduced uterine perfusion pressure rat model. Reprod Dev Med [serial online] 2019 [cited 2019 Aug 26];3:36-41. Available from: http://www.repdevmed.org/text.asp?2019/3/1/36/255987
| Introduction|| |
Preeclampsia (PE), a pregnancy-related disorder that complicates 5%–8% of pregnancies, is manifested as hypertension,, proteinuria, and edema. Hypertensive disorder of pregnancy is a leading cause of maternal and fetal morbidity and mortality throughout the world. PE affects multiple organ systems. To date, some simple preventive measures such as low-dose aspirin, low-molecular-weight heparin, calcium supplements, and diet and lifestyle interventions are used to provide a temporary relief from the symptoms. There is currently no cure for PE patients, and the most effective treatment option available so far is termination of pregnancy and removing the placenta.
Over the last two decades, “the two-stage theory” has been widely used to describe the pathogenesis of PE., In the first stage, suppression of trophoblast invasion leads to incomplete spiral artery remodeling and poor placental development. Poor spiral artery remodeling evokes ischemia–reperfusion injury, causing oxidative stress in placental villi. In the second stage, the placenta overproduces anti-angiogenic factors, which contributes to maternal endothelial dysfunction and leads to various clinical manifestations in mother, such as hypertension, kidney damage, and proteinuria. This theory suggests that the trophoblast invasion dysfunction plays an important role in the pathogenesis of PE.
Lin28 is an RNA-binding protein (RBP) first discovered in Caenorhabditis elegans. It can govern the developmental phases, stem cell self-renewal, cell differentiation, invasion, and embryonic growth., Studies have shown that Lin28 can serve as one of the embryonic stem cell markers because it is highly expressed in embryonic tissues, and its expression levels gradually decrease with cell differentiation. Other studies report a high expression of Lin28 in tumor tissues., There are two isoforms of Lin28, Lin28A, and Lin28B. Previous studies have suggested that Lin28B is involved in the pathogenesis of PE in humans. Lin28B is highly expressed in human placental tissue. With the progress of pregnancy, however, the expression levels of Lin28B are gradually decreased, suggesting that Lin28B may be involved in placental development and regulation of trophoblast proliferation and invasion in the earlier stages of pregnancy.
The reduced uterine perfusion pressure (RUPP) model is a widely used animal model in studies on pregnant animals including rats., It is a well-established model of PE in which the placental ischemia can be induced through surgical clipping of the abdominal aorta and uterine arteries. The RUPP rat model exhibits the physiological manifestations of PE in humans, including hypertension, proteinuria, and decreased fetal weight.,
In the present study, our objective was to establish a RUPP model in rats and verify that Lin28B plays an important role in the pathogenesis of PE in rats.
| Methods|| |
This study was approved by the Institutional Animal Care and Use Committee at China Medical University (2017PS347K). Male and female Sprague–Dawley rats were purchased from Liaoning Changsheng Biotechnology Co., Ltd. Animals were housed individually at 24°C under a 14 h/10 h light/dark cycle and fed a regular chow and water meal. At the age of 4 months, male and female rats were caged together at a ratio of 1:3, and gestation day (GD) 0 was defined as the day on which the sperm plugs were detected. Pregnant rats were randomly distributed among either RUPP or normal pregnant (NP) control groups.
Reduction in uterine perfusion pressure
On GD 14, rats were anesthetized with 10% chloral hydrate. Under aseptic conditions, an abdominal incision was made allowing for visualization of the abdominal aorta and exteriorization of the ovarian and utero–fetal placental vascular beds. The region of the abdominal aorta near the iliac bifurcation was carefully cleaned using cotton swabs to remove the periadventitial fat, and then separated from the vena cava. An iron wire (inside diameter = 0.3 mm) was placed parallel to the aorta, and a 4-0 silk braided ligature was tied around both the aorta and the iron wire. Once taut, the iron wire was removed from the knotted ligature, thus creating a constrictive band (outside diameter = 0.3 mm) and reducing blood flow through the aorta. This procedure reduces the uterine perfusion pressure in gravid rats by 40%. To block the compensatory blood flow from the ovarian side of the uterine circulation that may begin in response to constriction of the abdominal aorta, an iron wire (outside diameter = 0.1 mm) was used to create a constrictive band (inside diameter = 0.1 mm) and reduce blood flow through the right and left ovarian arteries. The control group consisted of mice subjected to a Sham surgery with similar abdominal incision and suturing.
Maternal blood pressure measurements
On GD 13, blood pressure was noninvasively measured (between 8 am and 10 am) by determining the tail blood volume with a volume pressure recording sensor and an occlusion tail cuff (Software BP-98A, Softron, Tokyo, Japan). However, the blood flow in the tail artery is reduced after the coarctation of abdominal aorta. Thus, the tail blood volume cannot reflect blood pressure changes accurately. On GD 20, animals were anesthetized with 10% chloral hydrate, and carotid arterial catheters were inserted for analyzing the blood pressure measurements. The carotid arterial catheter was connected to a pressure transducer attached to an amplifier and pressure recorder (Power Lab PL3508, AD Instruments, Sydney, Australia).
Urine protein analysis
Animals were placed in metabolic cages and provided with water without chow on GDs 12, 15, 17, and 19. The urine was collected, and the volume of urine collected in a day (from 10 am to 10 am on the next day) was recorded. Urine samples were spun at 670 ×g for 5 min at 4°C and stored at −20°C until processed. Urine protein quantitative assay kit (C035-2 CBB, Nanjing Institute of Bioengineering, China) was used to determine the amounts of proteins excreted in the urine. Optical density was calculated for each urine sample at 573 nm and multiplied by the volume of urine collected to determine the amount of proteins excreted in the urine during a period of 24 h.
On GD 20, under chloral hydrate anesthesia, a midline incision was made, the uterine horns were exposed, and the fetuses were harvested. The number of viable and resorbed fetuses in each rat was recorded along with individual fetal weight. Placental tissues were also excised and weighed, and then stored at −80°C until further analysis. For immunohistochemistry, tissue samples were excised, fixed in formalin, and embedded in paraffin. Resorption rate was calculated as percent fetal resorption = (number of resorbed fetuses/total number of fetuses) ×100.
Quantitative real-time polymerase chain reaction
Total RNA was extracted from placenta with Trizol (Invitrogen, Carlsbad, CA, USA) reagent according to the manufacturer's protocol. Reverse transcription reaction was performed using the PrimeScript RT Master Mix (Takara, Dalian, China) in a total volume of 20 μL. The newly synthesized cDNA was amplified by quantitative real-time polymerase chain reaction (qRT-PCR), and the analysis was carried out in ABI7500 qRT-PCR system (Applied Biosystems, Carlsbad, CA, USA) using SYBR Premix Ex Taq II (Takara, Dalian, China). Data were analyzed according to the comparative Ct (2−ΔΔta) method, and the mRNA expression values were normalized to the expression levels of β-actin mRNA. Primers used for qRT-PCR are listed in [Table 1].
Protein extracts were prepared from the placental tissues by homogenization in radio-immunoprecipitation assay (RIPA) lysis buffer. Protein concentration in the supernatant was determined using a protein assay kit (BCA, Beyotime, China). Protein extracts prepared from the placental tissues containing 30 μg of total protein were subjected to size fractionation by electrophoresis on 12% sodium dodecyl sulfate (SDS)-polyacrylamide gel. The fractionated proteins were transferred from the gel to activated polyvinylidene difluoride membrane by electroblotting. Membranes were incubated for 2 h at room temperature in skimmed milk for blocking excess protein-binding sites and then overnight at 4°C with anti-Lin28B (Cat. 16178-1-AP, Proteintech, 1:800) and anti-β-actin (Cat. 66009-1-Ig, Proteintech, 1:2,000) antibodies. Next day, the membranes were incubated with horse radish peroxidase-conjugated secondary antibody (goat anti-rabbit IgG or goat anti-mouse IgG; 1:2,000 dilution; Beijing Zhongshan Golden Bridge Biotechnology Co., Ltd, Beijing, China). Immunoreactive proteins were detected using chemiluminescence reagent (Thermo Scientific, Waltham, MA, USA) and visualized with Micro-Chemi (DNR Bio-Imaging Systems, Israel). All the experiments were repeated three times.
Tissue samples were fixed in 10% formalin, embedded in paraffin, and 4-μm-thick sections were cut. The samples were mounted on glass slides. The slides were bathed in xylene followed by gradually decreasing concentrations of ethanol and were further bathed in deionized water, 0.3% hydrogen peroxide solution, phosphate-buffered saline (PBS), and blocking serum. The anti-Lin28B antibody was diluted in blocking serum, and the slides were incubated overnight in the presence of antibody. The following day, slides were rinsed in PBS and incubated with streptavidin/peroxidase followed by 3, 3'-diaminobenzidine. The slides were then counterstained with hematoxylin and observed under Nikon microscope (Nikon, Ni-U, Tokyo, Japan). Images were analyzed and prepared using ImageJ software (NIH, USA).
Data were analyzed and plotted using GraphPad Prism version 7.0 (GraphPad software, Inc., San Diego, CA, USA). All the data were expressed as mean ± standard error of mean. The t-test was used to compare the data between the two groups. P < 0.05 was considered statistically significant.
| Results|| |
Changes of blood pressure and urine protein in reduced uterine perfusion pressure model rats
There were no significant differences in the blood pressure and urine protein among the two groups of rats on GD 13 (111.9 ± 5.38 mmHg vs. 110 ± 6.06 mmHg; 2.85 ± 1.33 mg/dl vs. 2.49 ± 1.77 mg/dl; NP vs. RUPP rats, respectively, P > 0.5). On GD 20, the blood pressure in RUPP rats was significantly elevated compared with that of the NP rats (3.3 ± 3.2 mmHg vs. 33.3 ± 3.3 mmHg; NP vs. RUPP rats, respectively, P < 0.001) [Figure 1]a, indicating that the RUPP initiated at GD 14 induced hypertension during pregnancy. RUPP model rats exhibited significantly elevated levels of 24-h urine protein levels compared to NP rats (3.79 ± 0.67 mg/dl vs. 8.82 ± 1.05 mg/dl; NP vs. RUPP rats, respectively, P < 0.001) [Figure 1]b.
|Figure 1: Changes of blood pressure and urine protein in RUPP model rats. (a) Blood pressure changes in RUPP model rats were significantly higher than that of NP rats on GD 20 (P < 0.001). (b) Urine protein changes in RUPP model rats were higher than that of NP rats on GD 20 (P < 0.001). RUPP: Reduced uterine perfusion pressure; NP: Normal pregnant; GD: Gestation day. *P < 0.001.|
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Effect on maternal and fetal weight in reduced uterine perfusion pressure model rats
There was no significant difference in the maternal weight on GD 13 (246.6 ± 15.58 g vs. 257.3 ± 16.74 g; NP vs. RUPP rats, respectively, P > 0.05). On GD 20, fetal resorption rate in case of RUPP model rats was much higher than that in NP rats (3.1% vs. 69.4%; NP vs. RUPP rats, respectively, P < 0.001). The fetal weight in RUPP group was significantly lower than that in the NP group (P < 0.001). The placental weight in RUPP model rats was also lower than that in NP rats [Table 2] and [Figure 2]; however, the differences were not found to be significant (P > 0.05).
|Table 2: Maternal and fetal characteristics in RUPP model rats and NP rats|
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|Figure 2: Effect on maternal and fetal weight in RUPP model rats. (a) Fetal weight changes in RUPP model rats were significantly lower than that of NP rats on GD 20 (P < 0.001). (b) Differences were not found of placental weight in two groups (P > 0.05). RUPP: Reduced uterine perfusion pressure; NP: Normal pregnant; GD: Gestation day. *P < 0.001.|
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Expression of Lin28B in the placenta of reduced uterine perfusion pressure model rats
To determine whether Lin28B expression levels are dysregulated in the placenta of RUPP model rats, immunohistochemical analysis of Lin28B was performed. Compared to NP rats, placenta from RUPP model rats exhibited decreased Lin28B expression in trophoblastic region [P < 0.05; [Figure 3]d,[Figure 3]e,[Figure 3]f. Furthermore, Lin28B mRNA and protein levels were also significantly decreased in the placenta of RUPP rats compared with the NP rats [P < 0.001; [Figure 3]a,[Figure 3]b,[Figure 3]c.
|Figure 3: The expression of Lin28B is decreased in the placenta of RUPP model rats. (a) qRT-PCR analysis for Lin28B mRNA expression in the placenta between RUPP model rats and NP rats (P < 0.001). (b-c) Western blot for Lin28B and β-actin in the placenta of RUPP model rats and NP rats. (d) Images of Lin28B immunostaining in the placenta of NP rats. (e) Images of Lin28B immunostaining in the placenta of RUPP model rates. (f) Expression of Lin28B immunostaining in the placenta of RUPP model rats and NP rats (P < 0.05). RUPP: Reduced uterine perfusion pressure; NP: Normal pregnant; qRT-PCR: Quantitative real-time polymerase chain reaction. *P < 0.001, †P < 0.05.|
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| Discussion|| |
Lin28B has well-established roles in cell development, differentiation, and tumorigenesis. Lin28B has been suggested to play a role in PE by reducing trophoblast invasion and syncytialization. However, the expression of Lin28B and its exact function in PE rats are unclear. In this study, we measured for the first time the levels of Lin28B expression, at both mRNA and protein levels, in the placental tissue of RUPP model rats. Our results show a significant decrease in Lin28B expression in the placenta of RUPP model rats.
PE is a common complication of pregnancy with unclear mechanisms. Abnormal trophoblast invasion leads to placental hypoperfusion, which is considered to be the initial cause of hypertensive disorders in pregnancy. The resultant placental ischemia can cause extensive damage and release of higher levels of vascular endothelin and thromboxane, thereby increasing sensitivity to angiotensin II, and reducing vasodilation substances such as nitric oxide and prostacyclin, causing the corresponding clinical symptoms.
Clinically, PE is treated by terminating pregnancy. The combination of studies involving animal models and human placental tissues can be used to provide a deeper understanding of the etiology and potential therapeutic interventions of PE. Various PE animal models have been established and have their specific characteristics.
The RUPP model is a well-characterized model for investigating PE. In addition to hypoxia, RUPP animals can also be induced to exhibit hypertension and proteinuria., Such models have been developed for various animals such as rats, sheep, rabbits, guinea pigs, and dogs., There are also other animal models of PE such as the ones in which L-NG-Nitroarginine methyl ester (L-NAME) can be used to induce the symptoms of PE by chronic nitric oxide synthase inhibition. However, dose-dependent hypertension observed in animals treated with L-NAME does not mimic placental signaling, which is thought to trigger human disease. Losartan can also be used to trigger PE in animals through the regulation of autoimmunity, and it can also generate corresponding pathological changes through the renin–angiotensin system, but it is not suitable for clinical use because it is teratogenic. Continuous cold stimulation increases the secretion of adrenaline and norepinephrine by stimulating the sympathetic nervous system; however, the same symptoms can be also observed in nonpregnant animals. Thus, the RUPP model of PE was chosen for the present study because the model can be very well used to establish the first stage of PE and can reduce the blood flow by as much as 40%, which is significant for the pathogenesis of PE.
Lin28 is a highly conserved RBP, which was first found in C. elegans and plays an important role in regulating the timing and spatial development of parasites. The earliest examination of Lin28 expression in human tissue was in placental tissue where it was observed in a great abundance as compared to any other organ. Lin28 mRNA is also present in mesenchymal stromal cells isolated from human amniotic and chorionic membranes. Lin28 has two paralogs, namely Lin28A and Lin28B. The expression of Lin28B in embryonic tissues is gradually decreased with cell differentiation. Lin28B overexpression was also observed in colorectal, lung, ovarian, breast, and esophageal cancers.,,,, These studies suggest that Lin28B is associated with tumor invasion and metastasis. Trophoblastic infiltration is similar to tumorigenesis. Previous studies report that Lin28B overexpression can increase HTR8 cell proliferation, migration, and invasion, whereas Lin28B knockdown has been shown to reduce cell proliferation in JEG3 cells. In addition, our unpublished clinical data suggest that the expression of Lin28B is negatively correlated with blood pressure but is positively correlated with the fetal weight. These findings illustrate that Lin28B is associated with the progress of PE.
This study used the RUPP method to construct a rat model of PE. On GD 20, the blood pressure and urine protein increased with a concomitant decrease in the fetal weights. It is similar with the PE phenotype in humans, suggesting that the reduction of placental blood flow can simulate the onset of PE. Normal pregnancy is accompanied by an adequate blood perfusion and trophoblastic infiltration of the placenta. However, PE is triggered when the placenta is poorly infiltrated by the trophoblast. By detecting the Lin28B index in rat placental tissue, we found that the expression levels of Lin28B in PE rats showed a significant decrement when compared with the NP rats. Our results are consistent with the levels of Lin28B detected in the placenta of pregnant women with PE. The data suggested that the expression of Lin28B is negatively correlated with blood pressure but positively correlated with fetal weights. We speculate that Lin28B may participate in PE in rats. However, the specific process of the PE in rats is not clear, and further experimentation is required in this direction.
In conclusion, this study demonstrates that placental ischemia in rats is associated with a significant increase in blood pressure and urine protein. Notably, these alterations were accompanied by a decrease in Lin28B expression. These data describe placental ischemia as a critical event for the development of pregnancy-related hypertension and suggest that Lin28B may be investigated as a target for the treatment of PE.
Financial support and sponsorship
This work was supported by the grants from the National Key Research and Development Program of China (2016YFC1000404), the National Natural Science Foundation of China (81370735, 81771610), and Shengjing Free Researcher Fund (201706).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]