Hypoxia-induced regulation of placental REDD1 and mTOR was impaired in a rat model of estrogen-induced cholestasis

Zhang, Fan; Chen, Huafang; Wang, Xiaodong; Yu, Pin; Hu, Yayi

doi:10.1007/s00404-016-4186-7

Cited by 3 publications

(7 citation statements)

References 29 publications

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“…However, no significant correlation was observed between Mrp2 expression and other parameters of in vivo MTX clearance (CL up,liver , CL urine and CL exc,urine ), suggestive of the absence of any association between Mrp2 and the process of hepatic uptake or urinary excretion of MTX. On the other hand, the renal expression of Oat3 was significantly correlated with CL up,kidney of MTX ( Figure 5 C, R = 0.998, p = 0.04), indicative of the involvement of Oat3 expression in the modulation of renal uptake of MTX [ 31 , 32 ].…”

Section: Resultsmentioning

confidence: 99%

Ursodeoxycholate Restores Biliary Excretion of Methotrexate in Rats with Ethinyl Estradiol Induced-Cholestasis by Restoring Canalicular Mrp2 Expression

Kim

Kang

Kwon

et al. 2018

IJMS

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The in vivo relevance of ursodeoxycholate (UDCA) treatment (100 mg/kg/day, per oral tid for 5 days before cholestasis induction followed by the same dosing for 5 days) on hepatic function was investigated in rats with 17α-ethinylestradiol (EE, 10 mg/kg, subcutaneous for 5 days)-induced experimental cholestasis. The bile flow rate and the expression level of hepatic multidrug resistance-associated protein 2 (Mrp 2) that were decreased in cholestasis were restored after UDCA treatment. Consistent with this, the biliary excretion clearance (CLexc,bile) of a representative Mrp2 substrate—methotrexate (MTX)—was decreased in cholestatic rats but was restored after UDCA treatment. Consequently, the plasma concentrations of MTX, which were increased by cholestasis, were decreased to control levels by UDCA treatment. Thus, the restoration of CLexc,bile appears to be associated with the increase in Mrp2 expression on the canalicular membrane by UDCA treatment followed by Mrp2-mediated biliary excretion of MTX. On the other hand, the hepatic uptake clearance (CLup,liver) of MTX was unchanged by cholestasis or UDCA treatment, suggestive of the absence of any association between the uptake process and the overall biliary excretion of MTX. Since UDCA has been known to induce the expression of canalicular MRP2 in humans, UDCA treatment might be effective in humans to maintain or accelerate the hepatobiliary elimination of xenobiotics or metabolic conjugates that are MRP2 substrates.

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Section: Resultsmentioning

confidence: 99%

Ursodeoxycholate Restores Biliary Excretion of Methotrexate in Rats with Ethinyl Estradiol Induced-Cholestasis by Restoring Canalicular Mrp2 Expression

Kim

Kang

Kwon

et al. 2018

IJMS

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“…Meanwhile, in our previous experiment, the placental levels of HIF-1a, marker of uterine-placental-fetal IR, were significantly elevated in pregnant rats of IR group compared with those in sham groups. 20 The liver levels of IkBa in EE-induced ICP rats were obviously decrease compared with the level in control pregnant rats. IkBa is the inhibitor of NF-kB and the compromised hepatic IkBa expression led to enhanced activity of NF-kB.…”

Section: Discussionmentioning

confidence: 87%

“…17,18 Studies indicated that mTOR, GLUT1, and their upstream regulator regulated the development of DNA damage response 1 (REDD1) 13,15,16 were dysregulated in placentas from both ICP patients and estrogen (EE)-induced ICP rats. 19,20 How immune and glycometabolism-related factors are expressed in liver tissues of ICP remains to be explored.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, glucose transporter type 1 (GLUT1), a downstream factor of mTOR, 15,16 serves as a basal glucose uptake factor in placental trophoblast cells and is essential for immune cell activation 17,18 . Studies indicated that mTOR, GLUT1, and their upstream regulator regulated the development of DNA damage response 1 (REDD1) 13,15,16 were dysregulated in placentas from both ICP patients and estrogen (EE)-induced ICP rats 19,20 . How immune and glycometabolism-related factors are expressed in liver tissues of ICP remains to be explored.…”

Section: Introductionmentioning

confidence: 99%

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Dysregulated Hepatic Expression of Glucose Transporter Type-1, Toll-Like Receptor 4, and Nuclear Factor Kappa B in Estrogen-Induced Cholestasis Pregnant Rats with Placental Ischemia-Reperfusion Stress

Zhang

Chen

Shan

et al. 2020

Maternal-Fetal Medicine

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Objective: This study aimed at investigating the expression of nuclear factor kappa B (NF-kB) and mammalian target of rapamycin (mTOR) related signal pathways in liver tissues of intrahepatic cholestasis of pregnancy animal models.Methods: Estrogen (EE)-induced cholestasis and a placental ischemia-reperfusion (IR) model were established in pregnant rats. All pregnant rats were divided into four groups by random number table: EE-IR group (n = 6), EE-sham group (n = 6), control-IR group (n = 6) and control-sham group (n = 6). Liver expression of mTOR, its upstream regulator DNA damage response-1 (REDD1), and downstream factor glucose transporter type-1 (GLUT1), accompanied by NF-kB (p65 is the most important component), its activator toll-like receptor 4 (TLR4), and inhibitor IkBa, were detected by western blot analysis and real-time polymerase chain reaction. The intergroup comparisons were performed with a one-way analysis of variance, the comparisons among groups were analyzed with the nonparametric Kruskal-Wallis test.Results: Giving pregnant rats EE alone reduced the hepatic expression of IkBa (0.72 ± 0.20 vs. 1.01 ± 0.07, P = 0.008). Meanwhile, giving pregnant rats placental IR alone increased liver levels of REDD1 (3.24 ± 0.98 vs. 1.06 ± 0.24, P = 0.025), GLUT1 (2.37 ± 0.82 vs. 1.09 ± 0.10, P = 0.039), TLR4 (2.12 ± 0.29 vs. 1.20 ± 0.28, P = 0.010), and p65 (2.09 ± 0.85 vs. 1.04 ± 0.06, P = 0.023), and decreased hepatic mTOR (0.50 ± 0.07 vs. 1.01 ± 0.03, P = 0.001) and IkBa (0.61 ± 0.08 vs. 1.01 ± 0.07, P = 0.014) expression. Subjecting EE-treated rats to placental IR did not further alter liver levels of GLUT1 (2.02 ± 0.45 vs. 1.79 ± 0.39, P = 0.240), TLR4 (2.10 ± 0.74 vs. 1.60 ± 0.36, P = 0.129), or p65 (2.41 ± 0.83 vs. 1.65 ± 0.46, P = 0.145), whereas it did decrease hepatic mTOR (0.42 ± 0.09 vs. 0.90 ± 0.14, P = 0.008) and IkBa (0.43 ± 0.09 vs. 0.72 ± 0.20, P = 0.004) expression and enhance REDD1 expression (4.46 ± 0.65 vs. 2.05 ± 0.47, P = 0.009). Placental IR stress did impact the hepatic expression of REDD1-mTOR-GLUT1 and TLR4/ NF-kB/IkBa in pregnant rats. Conclusion:Placental IR-induced hepatic GLUT1, TLR4, and p65 alternation, which responded efficiently in control rats, were impaired in EE-induced ICP rats.

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“…Body weights were monitored weekly. At the end of GD21, all rats were fasted overnight prior to being euthanized with chloral hydrate which was also used in previous studies ( 27 , 28 , 29 ). Blood samples of rats were obtained from the common abdominal aorta for measurements of insulin levels.…”

Section: Methodsmentioning

confidence: 99%

Effect of Maternal Obesity on Fetal Growth and Expression of Placental Fatty Acid Transporters

Zhang

et al. 2017

Jcrpe

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Objective:To explore the effects of maternal high-fat (HF) diet-induced obesity on fetal growth and the expression of placental nutrient transporters.Methods:Maternal obesity was established in rats by 8 weeks of pre-pregnancy fed HF diet, while rats in the control group were fed normal (CON) diet. Diet-induced obesity (DIO) rats and diet-induced obesity-resistant (DIR) rats were selected according to body weight gain over this period. After copulation, the CON rats were divided into two groups: switched to HF diet (CON-HF group) or maintained on the CON diet (CON-CON group). The DIO rats and DIR rats were maintained on the HF diet throughout pregnancy. Pregnant rats were euthanized at day 21 gestation, fetal and placental weights were recorded, and placental tissue was collected. Reverse transcription-polymerase chain reaction was used to determine mRNA expression of placental nutrient transporters. Protein expression was determined by Western blot.Results:Average fetal weight of DIO dams was reduced by 6.9%, and the placentas of CON-HF and DIO dams were significantly heavier than the placentas of CON-CON and DIR dams at day 21 of gestation (p<0.05). The fetal/placental weight ratio of DIO dams was significantly reduced compared with the fetal/placental weight ratio of CON-CON dams (p<0.05). The mRNA expression of GLUT-1 and SNAT-2 were not significantly different between groups. The mRNA and protein expression levels of CD36, FATP-1, and FATP-4 in DIO dams were decreased significantly (p<0.05).Conclusion:Maternal obesity induced by a HF diet led to intrauterine growth retardation and down-regulated the expression of placental fatty acid transporters.

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Hypoxia-induced regulation of placental REDD1 and mTOR was impaired in a rat model of estrogen-induced cholestasis

Cited by 3 publications

References 29 publications

Ursodeoxycholate Restores Biliary Excretion of Methotrexate in Rats with Ethinyl Estradiol Induced-Cholestasis by Restoring Canalicular Mrp2 Expression

Ursodeoxycholate Restores Biliary Excretion of Methotrexate in Rats with Ethinyl Estradiol Induced-Cholestasis by Restoring Canalicular Mrp2 Expression

Dysregulated Hepatic Expression of Glucose Transporter Type-1, Toll-Like Receptor 4, and Nuclear Factor Kappa B in Estrogen-Induced Cholestasis Pregnant Rats with Placental Ischemia-Reperfusion Stress

Effect of Maternal Obesity on Fetal Growth and Expression of Placental Fatty Acid Transporters

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