L-(+)-Ergothioneine Significantly Improves the Clinical Characteristics of Preeclampsia in the Reduced Uterine Perfusion Pressure Rat Model. Williamson Rachel D,McCarthy Fergus P,Manna Samprikta,Groarke Emer,Kell Douglas B,Kenny Louise C,McCarthy Cathal M Hypertension (Dallas, Tex. : 1979) Preeclampsia is a multifactorial hypertensive disorder of pregnancy founded on abnormal placentation, and the resultant placental ischemic microenvironment is thought to play a crucial role in its pathophysiology. Placental ischemia because of fluctuations in the delivery of oxygen results in oxidative stress, and recent evidence suggests that mitochondrial dysfunction may be a prime mediator. However, large clinical trials of therapeutic antioxidants such as vitamins C and E for the treatment of preeclampsia have been disappointing. L-(+)-ergothioneine (ERG)-an unusual amino acid betaine derived from histidine-has important cytoprotective and antioxidant properties under conditions of high oxidative stress. In this study, we investigated the potential therapeutic effects of administration of ERG in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. ERG (25 mg/kg per day) was administered to rats on gestational day 11. On gestational day 14, RUPP surgery was performed, and on gestational day 19, blood pressure (mean arterial pressure) and fetal growth were measured. Production of mitochondria-specific HO was analyzed in vivo in kidney samples. ERG ameliorated the hypertension (129±3 versus 115±4 mm Hg; =0.01; n=8) and significantly increased pup weight in RUPP rats. ERG also significantly decreased circulating levels of antiangiogenic sFlt-1 (soluble fms-like tyrosine kinase-1) in RUPP rats (1367±245 pg/mL; =0.04). Mitochondria-specific HO (0.022±0.003 versus 0.029±0.001; MitoP/B ratio, n=3; =0.05) was also significantly decreased in kidney tissue in RUPP rats treated with ERG. These data support the potential use of ERG for the treatment of preeclampsia. 10.1161/HYPERTENSIONAHA.119.13929
    Reduced mRNA Expression of RGS2 (Regulator of G Protein Signaling-2) in the Placenta Is Associated With Human Preeclampsia and Sufficient to Cause Features of the Disorder in Mice. Perschbacher Katherine J,Deng Guorui,Sandgren Jeremy A,Walsh John W,Witcher Phillip C,Sapouckey Sarah A,Owens Caitlyn E,Zhang Shao Yang,Scroggins Sabrina M,Pearson Nicole A,Devor Eric J,Sebag Julien A,Pierce Gary L,Fisher Rory A,Kwitek Anne E,Santillan Donna A,Gibson-Corley Katherine N,Sigmund Curt D,Santillan Mark K,Grobe Justin L Hypertension (Dallas, Tex. : 1979) Cascade-specific termination of G protein signaling is catalyzed by the RGS (regulator of G protein signaling) family members, including . Angiotensin, vasopressin, and endothelin are implicated in preeclampsia, and is known to inhibit G protein cascades activated by these hormones. Mutations in are associated with human hypertension and increased risk of developing preeclampsia and its sequelae. RGS family members are known to influence maternal vascular function, but the role of within the placenta has not been explored. Here, we hypothesized that reduced expression of within the placenta represents a risk factor for the development of preeclampsia. Although cAMP/CREB signaling was enriched in placentas from human pregnancies affected by preeclampsia compared with clinically matched controls and is known to be a CREB-responsive gene, mRNA was reduced in placentas from pregnancies affected by preeclampsia. Experimentally reducing expression within the feto-placental unit was sufficient to induce preeclampsia-like phenotypes in pregnant wild-type C57BL/6J mice. Stimulation of transcription within immortalized human HTR8/SVneo trophoblasts by cAMP/CREB signaling was discovered to be dependent on the activity of histone deacetylase activity, and more specifically, HDAC9 (histone deacetylase-9), and expression was reduced in placentas from human pregnancies affected by preeclampsia. We conclude that reduced expression of within the placenta may mechanistically contribute to preeclampsia. More generally, this work identifies as an -dependent CREB-responsive gene, which may contribute to reduced expression in placenta during preeclampsia. 10.1161/HYPERTENSIONAHA.119.14056
    Pregnancy-Related Acute Kidney Injury in Preeclampsia: Risk Factors and Renal Outcomes. Conti-Ramsden Frances I,Nathan Hannah L,De Greeff Annemarie,Hall David R,Seed Paul T,Chappell Lucy C,Shennan Andrew H,Bramham K Hypertension (Dallas, Tex. : 1979) Preeclampsia is a common cause of acute kidney injury (AKI) in low- and middle-income countries, but AKI incidence in preeclampsia, its risk factors, and renal outcomes are unknown. A prospective observational multicenter study of women admitted with preeclampsia in South Africa was conducted. Creatinine concentrations were extracted from national laboratory databases for women with maximum creatinine of ≥90 μmol/L (≥1.02 mg/dL). Renal injury and recovery were defined by Kidney Disease Improving Global Outcomes creatinine criteria. Predefined risk factors, maternal outcomes, and neonatal outcomes were compared between AKI stages. Of 1547 women admitted with preeclampsia 237 (15.3%) met AKI criteria: 6.9% (n=107) stage 1, 4.3% (n=67) stage 2, and 4.1% (n=63) stage 3. There was a higher risk of maternal death (n=7; relative risk, 4.3; 95% CI, 1.6-11.4) and stillbirth (n=80; relative risk, 2.2; 95% CI, 1.8-2.8) in women with AKI compared with those without. Perinatal mortality was also increased (89 of 240; 37.1%). Hypertension in a previous pregnancy was the strongest predictor of AKI stage 2 or 3 (odds ratio, 2.24; 95% CI, 1.21-4.17). Renal recovery rate reduced with increasing AKI stage. A third of surviving women (76 of 230 [33.0%]) had not recovered baseline renal function by discharge. Approximately half (39 of 76; 51.3%) of these women had no further creatinine testing post-discharge. In summary, AKI was common in women with preeclampsia and had high rates of associated maternal and perinatal mortality. Only two-thirds of women had confirmed renal recovery. History of a previous hypertensive pregnancy was an important risk factor. 10.1161/HYPERTENSIONAHA.119.13089
    Nitroso-redox balance and mitochondrial homeostasis are regulated by STOX1, a pre-eclampsia-associated gene. Doridot Ludivine,Châtre Laurent,Ducat Aurélien,Vilotte Jean-Luc,Lombès Anne,Méhats Céline,Barbaux Sandrine,Calicchio Rosamaria,Ricchetti Miria,Vaiman Daniel Antioxidants & redox signaling AIMS:Storkhead box 1 (STOX1) is a winged-helix transcription factor that is implicated in the genetic forms of a high-prevalence human gestational disease, pre-eclampsia. STOX1 overexpression confers pre-eclampsia-like transcriptomic features to trophoblastic cell lines and pre-eclampsia symptoms to pregnant mice. The aim of this work was to evaluate the impact of STOX1 on free radical equilibrium and mitochondrial function, both in vitro and in vivo. RESULTS:Transcriptome analysis of STOX1-transgenic versus nontransgenic placentas at 16.5 days of gestation revealed alterations of mitochondria-related pathways. Placentas overexpressing STOX1 displayed altered mitochondrial mass and were severely biased toward protein nitration, indicating nitroso-redox imbalance in vivo. Trophoblast cells overexpressing STOX1 displayed an increased mitochondrial activity at 20% O2 and in hypoxia, despite reduction of the mitochondrial mass in the former. STOX1 overexpression is, therefore, associated with hyperactive mitochondria, resulting in increased free radical production. Moreover, nitric oxide (NO) production pathways were activated, resulting in peroxynitrite formation. At low oxygen pressure, STOX1 overexpression switched the free radical balance from reactive oxygen species (ROS) to reactive nitrogen species (RNS) in the placenta as well as in a trophoblast cell line. INNOVATION:In pre-eclamptic placentas, NO interacts with ROS and generates peroxynitrite and nitrated proteins as end products. This process will deprive the maternal organism of NO, a crucial vasodilator molecule. CONCLUSION:Our data posit STOX1 as a genetic switch in the ROS/RNS balance and suggest an explanation for elevated blood pressure in pre-eclampsia. 10.1089/ars.2013.5661
    Increased serum strontium levels and altered oxidative stress status in early-onset preeclampsia. Barneo-Caragol Clara,Martínez-Morillo Eduardo,Rodríguez-González Susana,Lequerica-Fernández Paloma,Vega-Naredo Ignacio,Álvarez Francisco V Free radical biology & medicine BACKGROUND:Correctly distinguishing preeclampsia (PE), gestational hypertension (GH), and intrauterine growth retardation (IUGR) is a challenge for clinicians due to existing similarities. In our previous study, we showed that serum strontium (Sr) levels were elevated in preeclamptic women compared to healthy and GH pregnant women at the end of pregnancy. The main aim of this study was to evaluate Sr and oxidative stress in PE at the time of symptoms onset and before and compare it with IUGR/GH. METHODS:Samples collected at symptoms onset included 77 preeclamptic women and 72 women diagnosed with IUGR/GH divided into two groups according to the gestational extraction week (<34 and ≥ 34). Fifteen patients were also serialized until delivery. Samples collected before symptoms onset included 140 women who developed early-onset PE (E-PE, n = 9), late-onset PE (L-PE, n = 13), IUGR (n = 9), GH (n = 32) and no pathologies (n = 77). Strontium, placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), uric acid (UA), creatinine, lipid peroxidation, and total antioxidant activity (TAA) were measured. RESULTS:Mean Sr, sFlt-1/PIGF ratio, UA, and lipid peroxidation/TAA ratio levels were significantly higher (p = 0.002, <0.0001, <0.0001 and = 0.03, respectively) and estimated glomerular filtration rate (eGFR) and TAA significantly lower (p = 0.0008 and < 0.0001, respectively) in E-PE vs other pathologies when gestational extraction week was <34. There was a significant correlation between Sr and eGFR (r = 0.43, p = 0.02), sFlt-1/PIGF ratio (r = 0.56, p = 0.002), TAA and gestational week of sampling (r = -0.45, p = 0.02) and UA (r = -0.82, p < 0.0001) in the E-PE serial samples. No differences were found in Sr levels before symptoms onset. CONCLUSION:Serum Sr concentration and oxidative status are increased in E-PE when compared to other pathologies at the time of symptoms onset. More studies are needed to elucidate the causes of Sr levels elevation and its role in the pathophysiology of PE. 10.1016/j.freeradbiomed.2019.05.001
    Bisphenol A exposure alters placentation and causes preeclampsia-like features in pregnant mice involved in reprogramming of DNA methylation of WNT2. Ye Yunzhen,Tang Yao,Xiong Yu,Feng Liping,Li Xiaotian FASEB journal : official publication of the Federation of American Societies for Experimental Biology Preeclampsia leads to adverse outcomes for pregnant women. Bisphenol A (BPA) is an environmental endocrine disruptor and has been shown to be positively associated with increased risk of preeclampsia in human studies. We investigated whether BPA exposure causes preeclampsia-like features in pregnant mice and the associated underlying mechanisms. Experiments were performed in animal models and cell cultures. In pregnant mice, BPA-exposed mice exhibited preeclampsia-like features including hypertension, disruption of the circulation, and the placental angiogenesis biomarkers fms-related tyrosine kinase 1 and placenta growth factor, and glomerular atrophy; urinary protein was not affected. These preeclampsia-like features correlated with increased retention of smooth muscle cells and reduced vessel areas at the junctional zone of the placenta. In addition, there were disrupted expression of invasion-related genes including increased tissue inhibitors of metalloproteinases, decreased metalloproteinases, and Wnt family member WNT2/β-catenin, which correlated with increased DNA methylation in its promoter region and upregulation of DNA methyltransferase (Dnmt)1. BPA exposure impeded the interaction between the human cytotrophoblast cell line, HTR-8/SVneo, and endothelium cells. BPA exposure down-regulated WNT2 expression, and elevated the DNA methylation of WNT2; these results were consistent with in vivo observations. Inhibition of DNMT in HTR-8/SVneo cells resulted in reduced DNA methylation and increased expression of WNT2. Taken together, these data demonstrate that BPA exposure alters trophoblast cell invasion and causes abnormal placental vessel remodeling, both of which lead to the development of preeclampsia-like features in pregnant mice. Our results suggest that this phenomenon involves the epigenetic reprogramming and down-regulation of WNT2 mediated by DNMT1.-Ye, Y., Tang, Y., Xiong, Y., Feng, L., Li, X. Bisphenol A exposure alters placentation and causes preeclampsia-like features in pregnant mice involved in reprogramming of DNA methylation of WNT2. 10.1096/fj.201800934RRR
    Lipoxin A suppresses angiotensin II type 1 receptor autoantibody in preeclampsia via modulating caspase-1. Liu Haojing,Cheng Fangxiong,Xu Qiang,Huang Wei,Wang Sumei,Sun Rui,Ye Duyun,Zhang Dongxin Cell death & disease Preeclampsia (PE) remains a leading cause of maternal and neonatal morbidity and mortality. Numerous studies have shown that women with PE develop autoantibody, termed angiotensin II type 1 receptor autoantibody (AT1-AA), and key features of the disease result from it. Emerging evidence has indicated that inflammatory cell necrosis, such as pyroptosis, could lead to autoantigen exposure and stimulate autoantibody production. Caspase-1, the central enzyme of inflammasome and key target of pyroptosis, may play roles in AT1R exposure and AT1-AA production. Exploring endogenous regulator that could inhibit AT1-AA production by targeting pyroptosis will be essential for treating PE. Lipoxin A (LXA), endogenous dual anti-inflammatory and proresolving lipid mediator, may inhibit AT1-AA production via modulating caspase-1. Thus, we explore whether caspase-1 is essential for AT1-AA production and LXA inhibits AT1-AA via modulating caspase-1. PE patients and mice developed AT1-AA associated with caspase-1 activation. Caspase-1 deletion leaded to AT1-AA decrease in PE mice. Consistent with these findings, we confirmed caspase-1 activation, trophoblast pyroptosis and AT1R exposure in PE mice and trophoblast model, while caspase-1 deficiency showed decreased trophoblast pyroptosis and AT1R exposure in vitro and in vivo. Interestingly, LXA could suppress AT1-AA production via regulating caspase-1 as well as enhancing phagocytosis of dead trophoblasts by macrophages. These results suggest that caspase-1 promotes AT1-AA production via inducing trophoblast pyroptosis and AT1R exposure, while LXA suppresses AT1-AA production via modulating caspase-1, supporting caspase-1 serving as a therapeutic target for attenuating AT1-AA and LXA protecting patients from AT1-AA and PE. 10.1038/s41419-020-2281-y