CD4+ T cells cause renal and placental mitochondrial oxidative stress as mechanisms of hypertension in response to placental ischemia

Abstract

The Reduced Uterine Perfusion Pressure (RUPP) rat model and normal pregnant (NP) rat recipients of RUPP CD4+T cells recapitulate many characteristics of preeclampsia (PE) such as hypertension and oxidative stress. We have shown an important hypertensive role for NK cells to cause mitochondrial (mt) dysfunction in RUPP rats, however the role for RUPP CD4+ T cells to stimulate NK cells is unknown. Therefore, we hypothesize that RUPP induced CD4+ T cells activate NK cells to cause mt dysfunction/ROS as mechanisms of hypertension during pregnancy. We tested our hypothesis by adoptive transfer of RUPP CD4+T cells into NP rats or by inhibiting the activation of RUPP CD4+T cells with Orencia (Abatacept) and examining hypertension, NK cells and mt function. RUPP was performed on gestation day 14, splenic CD4+ T cells were isolated on GD19 and injected into NP rats on gestation day (GD) 13. In a separate groups of rats; Orencia was infused and the RUPP procedure performed. MAP and placental and renal mtROS increased in RUPP (n=7, p<0.05) and NP+RUPP CD4+ T cell recipients (n=13, p<0.05) compared to control NP (n=7) and NP+NPCD4+Tcell recipients (n=5), but was reduced with Orencia (n=13, p<0.05). Placental and renal respiration was reduced in RUPP (n=6, p<0.05) and NP+RUPP CD4+ T cells (n=6, state 3-p<0.05) compared to NP (n=5) and NP+NPCD4+Tcell recipients (n=5), but improved with Orencia (n=9, n=8 p<0.05). These data indicate that CD4+ T cells, independent of NK cells, cause mt dysfunction/ROS contributing to hypertension in response to placental ischemia during pregnancy.

Progesterone Induced Blocking Factor Reduces Hypertension and Placental Mitochondrial Dysfunction in Response to sFlt-1 during Pregnancy

“…This decrease in ATP and electron transport activity (ETC) reduces important cellular functions, leading to tissue damage and a change in organ homeostasis [ 20 ]. Our previous studies have demonstrated a role for mitochondrial dysfunction and oxidative stress in the kidney and placenta of the pregnant RUPP rat model of PE or in response to RUPP CD4+ T cells or TNF-α during pregnancy, indicating an important role for inflammation to mediate multi-organ mt ROS and dysfunction in association with hypertension in pregnant rats [ 21 , 22 , 23 , 24 ].…”

Low Dose of IL-2 Normalizes Hypertension and Mitochondrial Function in the RUPP Rat Model of Placental Ischemia

“…Notably, we demonstrated that the blockade of circulating AT1-AA from human PE sera was able to attenuate mtROS in HUVECS cultured with PE sera with and without AT1-AA blockade [23]. In addition to the AT1-AA, our lab has recently investigated the importance of mt oxidative stress in PE pathology, and has linked reduced vascular endothelial mt respiration and mtROS with the presence of CD4+ T cells stimulated in response to placental ischemia [23][24][25][26][27][28][29]. In a previous study from our groups, we showed that LD recombinant IL-2 improved T regs cell in RUPP rats.…”

“…Although this study investigated IL-2, there is still more to understand about preeclampsia and the other factors that contribute to this disease. In addition, multiple factors can induce placental mitochondrial ROS production, and for example, we have previously shown that natural killer cells [4] and CD4+ T cells [29] cause mitochondrial dysfunction in RUPP rats and endothelial cells incubated with RUPP serum exhibit mitochondrial ROS [6]. HUVECS treated with serum from PE women and incubated with MitoSOX Red indicated that serum from PE women contained circulating factors which contribute to mitochondrial dysfunction and an increase in mt ROS in cultured human vascular endothelial cells, thereby demonstrating that an increase in oxidative stress contributes to endothelial dysfunction [6,23].…”

Deficiency in CD4 T Cells Leads to Enhanced Postpartum Internal Carotid Artery Vasoconstriction in Mice: The Role of Nitric Oxide

“…During pregnancy this results in mid-gestational differences in heart rate and mean arteriolar pressure, thus suggesting that these cell subsets may influence systemic vascular biology in the mother both developmentally and during pregnancy ( Burke et al, 2011 ). While evidence suggests that deficiency in a certain subset of T cells with regulatory properties (Treg) is associated with preeclampsia ( Cerdeira et al, 2012 ; Przybyl et al, 2015 ) our expanding knowledge of the complexity of these T cell subsets is likely to reveal associations between this disease and several members of the CD4 family of T cells ( Ahn et al, 2020 ; Saigusa et al, 2020 ; Deer et al, 2021 ).…”