IL‐17 causes hypertension and multi‐organ tissue dysfunction which is attenuated with blockade of agonistic autoantibodies to the angiotensin II type I (AT1‐AA) receptor during pregnancy

Abstract

Preeclampsia (PE) is characterized by new onset hypertension, intrauterine growth restriction, multi-organ dysfunction, inflammatory cytokines and agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA). More recent studies demonstrate a role for mitochondrial (mt) dysfunction (decreased respiration and mt Reactive Oxygen Species) in the pathogenesis of the disease, however, causative factors for mt dysfunction are still being identified. We have shown IL-17 to cause hypertension, stimulate TH17 cells, AT1-AA and ROS in pregnant Sprague Dawley rats. We have also shown that AT1-AA inhibitory peptide, ‘n7AAc’, blocks AT1-AA activity and hypertension in rat models of PE. In this study, we tested the hypothesis that IL-17 induced hypertension is associated with renal and placental mt dysfunction which can be attenuated with AT1-AA blockade during pregnancy. IL-17 (150 pg/day i.p.) was infused via osmotic minipumps beginning on gestation day (GD) 14, in the presence or absence of ‘n7AAc’ (144 μg/day). Blood pressure (MAP) and mt function were measured on GD 19 and were compared to that of normal pregnant (NP) rats. MAP increased in response to IL-17 from 98±3 mmHg in NP(n=11) to 115.0±3 (n=8) in NP+IL-17 (p<0.001) and was lowered with ‘n7AAc’ (108 ±3 in IL17+‘n7AAc’ (n=7). Placental maximal respiration was decreased with IL-17 (4.58 ± 0.47 pmol of O2/sec/mg (n=5);p<0.05) compared to NP (15.8± 5.73 pmol of O2/sec/mg (n=3) which improved with ‘n7AAc’ (17.45± 1.88 pmol of O2/sec/mg (n=3); p<0.001). Placental mt ROS increased with IL-17 (142 ± 1.6 %fold change (n=3)) compared to NP (100 ± 4.05 %fold change (n=12)) and was lowered with ‘n7AAc’ (14.55 ± 0.6 %fold change (n=3)). Renal maximal respiration was decreased with IL-17 (86.4± 33.5 pmol of O2/sec/mg (n=5) compared to NP (262± 43.6 pmol of O2/sec/mg (n=6)) which improved with ‘n7AAc’ (399± 74.7 pmol of O2/sec/mg (n=3) p<0.05). However, renal mt ROS was decreased with IL-17 (69.4± 2.02 %fold change (n=6)) compared to NP (100± 2.8 %fold change (n=12)) and was even further decreased with ‘n7AAc’ (35.8 ± 2.02 %fold change (n=5)). These data demonstrate that IL-17 causes multi-organ mt dysfunction and hypertension during pregnancy, most of which is improved with blockade of AT1-AA.