72 IL-17 stimulates B cells to secrete AT1-AA in hypertension and multi-organ tissue dysfunction during pregnancy

Abstract

Preeclampsia (PE), new onset hypertension, is associated with intrauterine growth restriction, increased IL-17, agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA), and placental mitochondrial dysfunction (mt reactive oxygen species) during pregnancy. We have shown IL-17 to cause hypertension, stimulate TH17 cells and AT1-AA, in pregnant Sprague Dawley (SD) rats. Moreover we have 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 IL-17 induced hypertension is associated with renal and placental mt ROS and hypertension is attenuated by AT1-AA blockade in pregnant SD rats. To further examine the role of IL-17 to directly cause B cell activation and hypertension during pregnancy, we infused IL-17 into nude-athymic pregnant rats, which are devoid of all T cells. Blood pressure (MAP) was measured at day 19 (GD19) of gestation after 5 days of chronic IL-17 (GD14, 150 pg/day i.p. osmotic minipumps) with or without ‘n7AAc’ (144 ug/day) (i.p. osmotic minipumps, SD only), and was compared to the appropriate normal pregnant control rat (NP) rat. To determine mechanisms for the hypertension in Nude rats + IL-17, circulating B cell proliferation was determined. MAP significantly increased in response to chronic IL-17 from 98+3 mmHg in NPSD (n=11) to 115.0±3 (n=8) in NPSD+IL-17 (p<0.001) and was lower with ‘n7AAc’ (108 ±3 in IL17+’n7AAc’ (n=7)). Placental and renal mt ros were significantly increased with IL-17 infusion. MAP and pup weight were 97+3 mmHg (n=3) and 1.3+0.09 grams in nude-athymic control pregnant rats and was 113+2 mmHg; n=4; (p<0.05 compared to control nude) and 1.16 + 0.06g with IL-17 infusion. B cells were increased 50% with IL-17 and APRIL, a cytokine which promotes B cell survival was increased (1.78±0.33 ng/mL) in IL-17 treated Nude rats compared to Control Nudes (0.578±0.22 ng/mL). These studies indicate that B cells stimulating AT1-AA to cause renal and placental mt ROS are important mechanisms of IL-17 induced hypertension during pregnancy.