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

Am J Physiol Regul Integr Comp Physiol. 2015 Jul 1;309(1):R62-70. doi: 10.1152/ajpregu.00377.2014. Epub 2015 Apr 22.

Abstract

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-α (TNF-α). 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.

Keywords: HIF-1α; TNF-α; animal model; hypertension; pregnancy; proteinuria; sFLT-1; superimposed preeclampsia; uterine artery resistance.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arterial Pressure* / genetics
  • Disease Models, Animal
  • Female
  • Fetal Growth Retardation / genetics
  • Fetal Growth Retardation / physiopathology
  • Genetic Predisposition to Disease
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Kidney / metabolism
  • Kidney / pathology
  • Phenotype
  • Pre-Eclampsia / etiology
  • Pre-Eclampsia / genetics
  • Pre-Eclampsia / metabolism
  • Pre-Eclampsia / physiopathology*
  • Pregnancy
  • Proteinuria / genetics
  • Proteinuria / physiopathology
  • Rats, Inbred Dahl
  • Rats, Inbred SHR
  • Species Specificity
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism
  • Uterine Artery / physiopathology
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • Vascular Resistance

Substances

  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Tumor Necrosis Factor-alpha
  • Flt1 protein, rat
  • Vascular Endothelial Growth Factor Receptor-1