Development of Maternal Syndrome in the Dahl Salt‐Sensitive Rats Is Dependent on T Cells

Abstract

Preeclampsia (PE) is characterized by hypertension and proteinuria (maternal syndrome) during pregnancy. We previously demonstrated that Dahl SS rats fed low salt develop maternal syndrome relative to virgin controls. Since T cells are important to amplify salt‐sensitive hypertension, we tested the hypothesis that T cells mediate the development of maternal syndrome in the Dahl SS. We tested this hypothesis in two ways: 1) by utilizing Dahl SS rats lacking T cells, SSCD247−/− rats, to investigate their pregnancy phenotype and 2) by reconstituting T cells into SSCD247−/− rats via adoptive transfer of splenocytes from Dahl SS donors. Eight week old SSCD247−/− rats were implanted with radio‐telemeters for continuous measurement of mean arterial pressure (MAP) and allowed to recover for a week. In addition to measurement of MAP, overnight urine samples were collected for proteinuria analysis before mating and throughout pregnancy. SSCD247−/− rats were mated with same age and strain males and virgin controls were run in parallel. In contrast to pregnant SS which demonstrate elevated blood pressure and proteinuria in pregnancy, the increase in protein excretion in late pregnancy relative to baseline (52.2±8 vs 23.4±3.6 mg/day, p<0.05, n=10/group) in mated SSCD247−/− rats is significantly less than in the pregnant SS. Moreover, the increased protein excretion is accompanied with a significant decrease in MAP at gestational day 20 from (117±2mmHg) compared to the virgin SSCD247−/− at gestational day 20 (132±4mmHg, p<0.0001). The blunted proteinuria and decreased MAP in the SSCD247−/− compared to the SS suggests that T cells mediate the maternal syndrome in the SS. To further interrogate the role of T cells in the pathogenesis of maternal syndrome, we reconstituted T cells in SSCD247−/− rats via adoptive transfer of splenocytes (~10 million) from SS rats by intraperitoneally injection at postnatal day 5 before the thymus was fully formed. The recipients designated for the mated group were mated at 8 weeks of age with SSCD247−/− rats. Animals underwent the same protocol as previously mentioned. At baseline, there was no significant difference in protein excretion between recipient virgin and mated groups (44.1±7.5 vs. 27.0±5.6 mg/day, p>0.05) or MAP (122±5 vs. 121±4 mmHg, p>0.05, n=5/group). The mated recipients develop a pregnancy‐specific increase in protein excretion throughout pregnancy that is absent in the virgin controls (100.9±8 vs. 53.3±6 mg/day, p<0.01). Despite the proteinuria, not all mated SSCD247−/− receiving the splenocyte transfer developed increased MAP; however, there was a significant increase in infiltrating leukocytes into the kidneys with ~7% of CD3+ T cells, which were primarily CD4+ T cells (~70%). Interestingly, a direct comparison of the mated recipients compared to the mated SSCD247−/− rats reveals that introducing T cells into the SSCD247−/− rat is sufficient to induce a maternal syndrome‐like level of proteinuria, highlighting the importance of T cells as a mechanism of maternal syndrome.Support or Funding InformationSupported by HL116264, 18POST33990140 and 15SFRN2391002