RUPP Th17s cause Hypertension and Mitochondrial Dysfunction in the Kidney and Placenta during Pregnancy

Abstract

Abstract BACKGROUND Preeclampsia (PE), new-onset hypertension (HTN), and organ dysfunction during the second half of pregnancy, is associated with an increase in inflammatory immune cells, including T helper 17 (Th17) cells. Studies have demonstrated that mitochondrial (mt) dysfunction is important in the pathogenesis of PE though causative factors have yet to be fully identified. Although Th17 cells, natural killer (NK) cells, and mt dysfunction contribute to HTN in the reduced uterine perfusion pressure (RUPP) rat model, the role of Th17 cells or IL-17 in mt dysfunction is unknown. Therefore, we hypothesize that RUPP stimulated Th17 cells cause HTN and mt dysfunction, which is alleviated with the blockade of IL-17. METHODS On gestational day 12 (GD12), RUPP Th17 cells were transferred into normal pregnant (NP) Sprague Dawley rats. A subset of NP + RUPPTh17 rats received IL-17RC (100pg/day) on GD14-19. Blood pressure (MAP), NK cells, and mt function were measured on GD19 in all groups. RESULTS MAP increased in response to NP + RUPP Th17 compared to NP rats and was lowered with IL-17RC. Circulating and placental NK cells increased with NP + RUPP Th17 compared to NP and were lowered with IL-17RC. Renal mtROS increased in NP + RUPP Th17 compared to NP and was normalized with IL-17RC. Similar to PE women, placental mtROS decreased in NP + RUPP Th17 and was normalized with IL-17RC. CONCLUSION Our results indicate that IL-17RC inhibition normalizes HTN, NK cell activation, and multi-organ mt dysfunction caused by Th17 cells stimulated in response to placental ischemia.