Renal natural killer cell activation and mitochondrial oxidative stress; new mechanisms in AT1-AA mediated hypertensive pregnancy

Abstract

Women with preeclampsia (PE) have increased mean arterial pressure (MAP), natural killer (NK) cells, reactive oxygen species (ROS), and agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). AT1-AA’s administered to pregnant rodents produces a well-accepted model of PE. However, the role of NK cells and mitochondrial reactive oxygen species (mtROS) in AT1-AA mediated hypertension during pregnancy is unknown. We hypothesize that AT1-AA induced model of PE will exhibit elevated MAP, NK cells, and mtROS; while inhibition of the AT1-AA binding to the AT1R would be preventative. Pregnant rats were divided into 4 groups: normal pregnant (NP) (n = 5), NP + AT1-AA inhibitory peptide (NP +‘n7AAc’) (n = 3), NP + AT1-AA infused (NP + AT1-AA) (n = 10), and NP + AT1-AA +‘n7AAc’ (n = 8). Day 13, rats were surgically implanted with mini-pumps infusing either AT1-AA or AT1-AA +‘n7AAc’. Day 19, tissue and blood was collected. MAP was elevated in AT1-AA vs. NP (119 ± 1 vs. 102 ± 2 mmHg, p < 0.05) and this was prevented by ‘n7AAc’ (108 ± 3). There was a 6 fold increase in renal activated NK cells in AT1-AA vs NP (1.2 ± 0.4 vs. 0.2 ± 0.1% Gated, p = 0.05) which returned to NP levels in AT1-AA +‘n7AAc’ (0.1 ± 0.1% Gated). Renal mtROS (317 ± 49 vs. 101 ± 13% Fold, p < 0.05) was elevated with AT1-AA vs NP and was decreased in AT1-AA +‘n7AAc’ (128 ± 16, p < 0.05). In conclusion, AT1-AA’s increased MAP, NK cells, and mtROS which were attenuated by AT1-AA inhibition, thus highlighting new mechanisms of AT1-AA and the importance of drug therapy targeted to AT1-AAs in hypertensive pregnancies.

Kidney Injury Caused by Preeclamptic Pregnancy Recovers Postpartum in a Transgenic Rat Model

“…These observations go along with studies that outline elevated ROS and impaired mitochondrial function in pregnancy in the kidney of other PE models [28,30]. It has been shown that agonistic autoantibodies (AT1-AA), which occur in the plasma of preeclamptic women, are associated with ROS production in different tissues including the kidney [28,38]. In our rat model for PE, most renal alterations recovered postpartum.…”

“…We observed mild changes in the expression of oxidative stress marker genes (Ncf-4, Nox-4) in the kidney during PE. These observations go along with studies that outline elevated ROS and impaired mitochondrial function in pregnancy in the kidney of other PE models [28,30]. It has been shown that agonistic autoantibodies (AT1-AA), which occur in the plasma of preeclamptic women, are associated with ROS production in different tissues including the kidney [28,38].…”

“…The blood pressure remained normotensive until the end of the study and four weeks postpartum (Figure 1B). WT rats were measured on single days (d0, 9,15,19,28,35,42,49) to enable comparison. The mean arterial blood pressure was at 105.3 ± 4.6 mmHg in WT rats during pregnancy and at 148.4 ± 20.7 mmHg in preeclamptic pregnant rats, respectively.…”

“…In the reduced uterine perfusion pressure (RUPP) rat model for PE, the renal impairment could be restored by vascular endothelial growth factor (VEGF) treatment [25,26]. Further, an important mechanism in preeclamptic renal injury seems to be an increased oxidative and inflammatory stress, leading to increased reactive oxygen species (ROS) production and complement activation [27][28][29][30]. Although these mechanisms cause severe renal alterations during pregnancies, there is lack of knowledge whether renal impairment is present postpartum in the PE animal model.…”

Superagonistic CD28 protects against renal ischemia injury induced fibrosis through a regulatory T-cell expansion dependent mechanism

“…Oxidative stress is known to have detrimental effects on T cells and natural killer (NK) cells both in chronic inflammatory conditions and in cancer [16]. Tregs have been reported to possess anti-oxidative capacity in the cancer microenvironment [17], therefore, we checked the expression of DNA associated oxidative stress marker, 8-Oxoguanine (8-OHdg) among different groups.…”