T Lymphocytes Contribute to the Development of Maternal Syndrome in Dahl SS Rats Maintained on a Low Salt Diet

Abstract

Preeclampsia (PE) is a pregnancy‐specific disorder that is characterized by hypertension and proteinuria (maternal syndrome) developing after the 20th week of gestation. Furthermore, women with preexisting hypertension or chronic kidney disease have an increased risk for developing PE. The exact mechanism(s) responsible for the pathogenesis of PE remain undetermined. The current postulate is thought to be a two‐step process: 1) improper placentation and remodeling of the spiral arteries and 2) development of maternal syndrome. Many animal models that investigate this mechanism require either a surgical or pharmacologic intervention to develop PE‐like phenotypes; however, it has been shown that the Dahl salt‐sensitive (SS) rat develops a PE‐like phenotype when maintained on a low salt diet. The Dahl SS rat is a well‐established model of salt‐sensitive hypertension and renal disease in response to a high salt challenge. Research from our laboratory has demonstrated that the immune system amplifies the disease process, and SSCD247−/− rats, SS rats which lack functional T lymphocytes, exhibit an attenuation in the hypertensive and renal damage phenotype. Taking these aspects into consideration, we tested the hypothesis that Dahl SS rats maintained on a 0.4% NaCl diet develop a pregnancy‐specific increase in blood pressure and proteinuria (maternal syndrome) that is attenuated in the absence of T lymphocytes. To test this hypothesis radio‐telemeters were implanted in female Dahl SS and SSCD247−/− rats (n=4/group) at 8 weeks of age for the continuous measurement of mean arterial pressure (MAP). After a week of recovery, animals were divided into groups of either virgin control or mated rats. The rats designated for the mated group were placed with male rats of the same strain and age. In addition to measurement of MAP, overnight urine samples were collected for proteinuria analysis before and throughout pregnancy. While there was no difference in baseline MAP between SS virgin and SS mated rats (122±2 vs 128±2 mmHg, P>0.05), mated rats exhibited a significant increase in MAP compared to SS virgin controls at gestational day (GD) 20 (129±4 vs 143±2 mmHg, P<0.05). Additionally, baseline protein excretion was comparable between SS virgin and SS mated (27±10 vs 49±12 mg/day, P>0.05), yet protein excretion was significantly increased in SS mated rats at GD20 versus SS virgin rats (131±24 vs 39±8 mg/day, P<0.05). Interestingly, when these studies were repeated in SSCD247−/− rats, there was a reduction in both MAP and proteinuria at GD20 compared to SS mated rats (121±1 vs 143±2 mmHg, 42±9 vs 131±24 mg/day, respectively, P<0.05). This protection from maternal syndrome in the SSCD247−/− rats was associated with a reduction in infiltrating immune cells measured via flow cytometry in both the kidneys and placentas compared to SS mated rats. We observed pregnancy‐specific increases in MAP and proteinuria that are associated with increased infiltration of T lymphocytes into renal and placental tissues. This phenotype is consistent with what is observed in clinical settings, and this model provides a unique opportunity to study the whole disease process of PE.Support or Funding InformationSupported by DK96859, HL116264, and 15SFRN2391002.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.