The Dahl salt-sensitive rat is a spontaneous model of superimposed preeclampsia

Gillis, Ellen E.; Williams, Jan Michael; Garrett, Michael R.; Mooney, Jennifer; Sasser, Jennifer M.

doi:10.1152/ajpregu.00377.2014

Cited by 80 publications

(82 citation statements)

References 54 publications

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“…Normally over the course of pregnancy, the Dahl S rat exhibits an increase in proteinuria 12 , as shown in Figure 2A. However, urinary protein excretion remained unchanged throughout the course of pregnancy in the treated Dahl S rats, resulting in a significant difference between groups during mid and late pregnancy.…”

Section: Resultsmentioning

confidence: 90%

“…Sildenafil citrate (BIOTANG, Inc.) was administered at 50 mg/kg/day to a subset of rats in a gel diet beginning on gestational day (GD) 10 through GD 20. Blood pressure was measured via telemetry 9 , and uterine artery resistance was measured via Doppler ultrasound 12 . On GD 20, rats were anesthetized for tissue collection, and renal histology and biochemical assays were performed as previously described 12,13 .…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies in our lab have shown that the Dahl Salt Sensitive (Dahl S) rat spontaneously exhibits a preeclamptic phenotype during pregnancy, characterized by increased blood pressure, severe exacerbation of proteinuria, increased fetal demise, and decreased pup size 12 . In this study, we tested the hypothesis that sildenafil treatment beginning on gestational day (GD) 10 (mid pregnancy in the rat) would improve fetal outcomes and ameliorate the maternal syndrome in this model of superimposed preeclampsia.…”

Section: Introductionmentioning

confidence: 99%

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Sildenafil Treatment Ameliorates the Maternal Syndrome of Preeclampsia and Rescues Fetal Growth in the Dahl Salt–Sensitive Rat

et al. 2016

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Preeclampsia, a hypertensive disorder of pregnancy, is detrimental to both mother and fetus. There is currently no effective treatment, but sildenafil, a phosphodiesterase-5 inhibitor, has been proposed as a potential therapy to reduce blood pressure and improve utero-placental perfusion in preeclamptic patients. We hypothesized that sildenafil would improve the maternal syndrome and fetal outcomes in the Dahl S rat model of superimposed preeclampsia. Dahl S rats were mated, and half received sildenafil (50 mg/kg/day, via food) from day 10 through day 20 of pregnancy. The untreated Dahl S rats had a significant rise in blood pressure and a 2-fold increase in urinary protein excretion from baseline to late pregnancy; however, sildenafil-treated Dahl S rats exhibited ~40 mmHg drops in blood pressure with no rise in protein excretion. Sildenafil also increased creatinine clearance and reduced nephrinuria and glomerulomegaly. Sildenafil treatment reduced the uterine artery resistance index during late pregnancy in the Dahl S rat and improved fetal outcomes (survival, weight, and litter size). Additionally, 19% of all pups were resorbed in untreated rats, with no incidence of resorptions observed in the treated group. Furthermore, TNF-α, endothelin-1, and oxidative stress, which are characteristically increased in women with preeclampsia and in experimental models of the disease, were reduced in treated rats. These data suggest that sildenafil improves the maternal syndrome of preeclampsia and blood flow to the fetoplacental unit, providing preclinical evidence to support the hypothesis that PDE-5 inhibition may be an important therapeutic target for the treatment of preeclampsia.

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Section: Resultsmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sildenafil Treatment Ameliorates the Maternal Syndrome of Preeclampsia and Rescues Fetal Growth in the Dahl Salt–Sensitive Rat

et al. 2016

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“…Recently, Gillis et al [64] and Takashima [65] described the pregnant Dahl salt sensitive rat as a spontaneous model of superimposed preeclampsia. Certainly, the non-pregnant Dahl SS rat is hypertensive, and feeding a high salt diet initiates a sequence of events leading to severe hypertension, lymphocyte infiltration into the kidney and proteinuria [66].…”

Section: The Complement System In Stage 1 Of Placental Preeclampsiamentioning

confidence: 99%

The Complement System and Preeclampsia

2017

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Purpose of review Preeclampsia affects 3–4% of pregnancies with few treatment options to reduce maternal and fetal harm. Recent evidence that targeting the complement system may be an effective therapeutic strategy in prevention or treatment of preeclampsia will be reviewed. Recent findings Studies in humans confirm the safety and efficacy of C5 blockade in complement-mediated disorders of pregnancy, including preeclampsia. Animal models mimic the placental abnormalities, and/or the maternal symptoms, which characterize preeclampsia. These models in mouse and rat have defined a role for complement and its regulators in placental dysfunction, hypertension, proteinuria, endothelial dysfunction, fetal growth restriction and angiogenic imbalance, thus informing future human studies. Summary Targeting excessive complement activation, particularly the terminal complement complex (C5b-9) and C5a may be an effective strategy to prolong pregnancy in women with preeclampsia. Continued research is needed to identify the initiator(s) of activation, the pathways involved and the key component(s) in the pathophysiology to allow development of safe and effective therapeutics to target complement without compromising its role in homeostasis and host defense.

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“…This is because the symptoms in the RUPP model are induced after midpregnancy. However, a spontaneous model of superimposed PE in the Dahl salt-sensitive rat has been evaluated (60). These animals have hypertension before pregnancy and develop dramatic pregnancy-induced increases in blood pressure all the while being maintained on normal-salt rodent chow compared with spontaneously hypertensive rats (SHR) that are hypertensive before pregnancy and normotensive Sprague-Dawley controls.…”

Section: Mice (Having Nk Cells But Not T or B Lymphocytes) Into Balb/mentioning

confidence: 99%

Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

Spradley

Palei

Granger

2015

American Journal of Physiology-Regulatory, Integrative and Comp

115

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) is a pregnancy-specific disorder typically presenting as new-onset hypertension and proteinuria. While numerous epidemiological studies have demonstrated that obesity increases the risk of PE, the mechanisms have yet to be fully elucidated. Growing evidence from animal and human studies implicate placental ischemia in the etiology of this maternal syndrome. It is thought that placental ischemia is brought about by dysfunctional cytotrophoblast migration and invasion into the uterus and subsequent lack of spiral arteriole widening and placental perfusion. Placental ischemia/ hypoxia stimulates the release of soluble placental factors into the maternal circulation where they cause endothelial dysfunction, particularly in the kidney, to elicit the clinical manifestations of PE. The most recognized of these factors are the anti-angiogenic sFlt-1 and pro-inflammatory TNF-␣ and AT1-AA, which promote endothelial dysfunction by reducing levels of the provasodilator nitric oxide and stimulating production of the potent vasoconstrictor endothelin-1 and reactive oxygen species. We hypothesize that obesity-related metabolic factors increase the risk for developing PE by impacting various stages in the pathogenesis of PE, namely, 1) cytotrophoblast migration and placental ischemia; 2) release of soluble placental factors into the maternal circulation; and 3) maternal endothelial and vascular dysfunction. This review will summarize the current experimental evidence supporting the concept that obesity and metabolic factors like lipids, insulin, glucose, and leptin affect placental function and increase the risk for developing hypertension in pregnancy by reducing placental perfusion; enhancing placental release of soluble factors; and by increasing the sensitivity of the maternal vasculature to placental ischemia-induced soluble factors. body mass index; inflammation; placental ischemia; pregnancy; RUPP; sFlt-1 PE IS A PREGNANCY-SPECIFIC DISORDER typically identified by new-onset hypertension in the second half of pregnancy. Although often accompanied by new-onset proteinuria, PE can be associated with many other signs and symptoms including headaches, visual disturbances, epigastric pain, and the development of edema (4,192). Globally, this disease affects over 8 million pregnancies per year and is estimated to account for 40 -60% of maternal deaths in developing countries (125). In the United States, there was a 25% increase in the rate of PE between the years 1987-2004 (189). This significant increase highlights the importance of understanding how risk factors like obesity play a role in the pathogenesis of this maternal syndrome. Obesity is defined as a body mass index (BMI) of greater than or equal to 30 kg/m 2 . Greater than one-half of pregnant women are overweight or obese (48), and more than two-thirds of reproductive-aged women in the United States are overweight or obese (49). Although mounting epidemiological evidence supports obesity as a major risk factor for PE, the mechanisms linking these two morbidities are...

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The Dahl salt-sensitive rat is a spontaneous model of superimposed preeclampsia

Cited by 80 publications

References 54 publications

Sildenafil Treatment Ameliorates the Maternal Syndrome of Preeclampsia and Rescues Fetal Growth in the Dahl Salt–Sensitive Rat

Sildenafil Treatment Ameliorates the Maternal Syndrome of Preeclampsia and Rescues Fetal Growth in the Dahl Salt–Sensitive Rat

The Complement System and Preeclampsia

Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

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