The Dahl salt-sensitive rat is a spontaneous model of superimposed preeclampsia. Am J Physiol Regul Integr Comp Physiol 309: R62-R70, 2015. First published April 22, 2015 doi:10.1152/ajpregu.00377.2014.-The mechanisms of the pathogenesis of preeclampsia, a leading cause of maternal morbidity and death worldwide, are poorly understood in part due to a lack of spontaneous animal models of the disease. We hypothesized that the Dahl salt-sensitive (S) rat, a genetic model of hypertension and kidney disease, is a spontaneous model of superimposed preeclampsia. The Dahl S was compared with the Sprague-Dawley (SD) rat, a strain with a well-characterized normal pregnancy, and the spontaneously hypertensive rat (SHR), a genetic model of hypertension that does not experience a preeclamptic phenotype despite preexisting hypertension. Mean arterial pressure (MAP, measured via telemetry) was elevated in the Dahl S and SHR before pregnancy, but hypertension was exacerbated during pregnancy only in Dahl S. In contrast, SD and SHR exhibited significant reductions in MAP consistent with normal pregnancy. Dahl S rats exhibited a severe increase in urinary protein excretion, glomerulomegaly, increased placental hypoxia, increased plasma soluble fms-like tyrosine kinase-1 (sFlt-1), and increased placental production of tumor necrosis factor-␣ (TNF-␣). The Dahl S did not exhibit the expected decrease in uterine artery resistance during late pregnancy in contrast to the SD and SHR. Dahl S pups and litter sizes were smaller than in the SD. The Dahl S phenotype is consistent with many of the characteristics observed in human superimposed preeclampsia, and we propose that the Dahl S should be considered further as a spontaneous model to improve our understanding of the pathogenesis of superimposed preeclampsia and to identify and test new therapeutic targets for its treatment.pregnancy; hypertension; proteinuria; uterine artery resistance; animal model; superimposed preeclampsia; TNF-␣; HIF-1␣; sFLT-1 PREECLAMPSIA is characterized by hypertension, proteinuria, and endothelial dysfunction after the twentieth week of pregnancy. Preeclampsia is currently among the leading causes of maternal morbidity and death worldwide, affecting approximately 5% of all pregnancies in the United States (35, 38). Preexisting chronic hypertension or chronic kidney disease dramatically increases the risk of developing superimposed preeclampsia during pregnancy, with an estimated 25% of chronically hypertensive women (39) and 30% of women with chronic kidney disease (23) developing superimposed preeclampsia. Furthermore, women with superimposed preeclampsia have an even greater risk of adverse maternal and fetal outcomes compared with women with de novo preeclampsia (8). Despite the severity and incidence of this disease, the mechanisms of the pathogenesis of preeclampsia remain unclear. There is currently no effective treatment available, and the only known "cure" for preeclampsia is the delivery of the placenta. There is also a potential for consequences o...

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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Preeclampsia (PE), increased BP and proteinuria during pregnancy, is detrimental to mother and fetus. There is currently no cure, and the development of new animal models is necessary to further research in this field. Here we test the hypothesis that the Dahl S rat, a known genetic model of hypertension and kidney disease, is also a spontaneous model of preeclampsia. Female Dahl S rats were implanted with a telemetry unit via the femoral artery. After a 10 day recovery period, baseline BP was recorded. Rats were placed in metabolic cages for 24 hr urine collection at baseline, mid and late pregnancy (days 10‐11, 17‐18), and urinary protein, 8‐isoprostane, and TBARS concentrations were measured via commercial assays as increased oxidative stress is also associated with preeclampsia. There was no difference in baseline BP (152±1.33 mmHg vs 151±4.2 mmHg) or proteinuria (61±9.6 mg/d vs 60±16.8 mg/d) in the pregnant rats vs virgin rats (n=5‐7). Pregnant rats exhibited increases in BP, proteinuria (Table), urinary 8‐isoprostane excretion (13.46±2.34 vs 3.14±0.52 ng/d*) and urinary TBARS excretion (224.43±31.00 vs 140.47±7.70 μmol/d, p=0.06) during late pregnancy, but no changes were observed in age‐matched virgin rats. In addition, the Dahl S rat has a smaller litter size compared to the Sprague Dawley (6.6±2.3 vs 14.4±1.9*) and exhibits intrauterine growth restriction as measured by pup weight on day 20 (1.86±0.10 vs 2.43±0.03 g*). These data suggest that the Dahl S rat has increased oxidative stress during pregnancy, possibly contributing to the exacerbation of hypertension and proteinuria during pregnancy in this strain. Mean Arterial Pressure (mmHg)Urinary Protein Excretion (mg/d)Baseline152±161±10Mid‐Pregnancy161±2*149±26*Late‐Pregnancy160±2159±48*p<0.05 vs baseline