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Inhibition of Angiotensin II Type 1 Receptor Agonistic Autoantibody Binding Improves Maternal Outcomes in Rats with Placental Ischemia
Author(s) -
Cunningham Mark Wayne,
Castillo Javier,
Vaka Venkata Ramana,
Amaral Lorena,
Cornelius Denise,
Spradley Frank,
Ibrahim Tarek,
Campbell Nathan,
Usry Nathan,
Williams Jan,
LaMarca Babbette
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.851.9
Subject(s) - endocrinology , medicine , preeclampsia , angiotensin ii receptor type 1 , angiotensin ii , blood pressure , gestation , chemistry , pregnancy , biology , genetics
Women with preeclampsia (PE) have hypertension, placental ischemia, reduced glomerular filtration rate (GFR), nitric oxide bioavailability, elevated sFlt, preproendothelin (PPE), agonistic Angiotensin II type 1 receptor autoantibodies (AT1‐AA), oxidative stress, and activation of cytolytic natural killer (NK) cells during pregnancy. The reduce uterine perfusion pressure (RUPP) rat model of placental ischemia displays these same characteristics, indicating that it is a good model to examine factors contributing to the pathophysiology of PE. We hypothesis that administration of a specific 7 amino acid peptide sequence (7AA) to inhibit the AT1‐AA from binding to the AT1receptor, will improve maternal blood pressure and other PE features in RUPP rats. Methods Day 14 of gestation RUPP rats receive the AT1‐AA inhibitory peptide, 7AA, (2ug/μl saline) via mini‐osmotic pump. On day 19 of gestation, conscious blood pressure (MAP) and GFR were determined. The blood, kidneys, and placentas were collected for molecular analysis and flow cytometry quantification of NK cells. Results MAP was elevated in RUPP rats (n=28) vs. normal pregnant (NP) rats (n=10) (121±1 mmHg vs 98±3 mmHg, p<0.05) and this hypertension was attenuated with 7AA (n= 15; 104±3 mmHg, p<0.05). Circulating sFlt1 (176±37 vs. 77±15pg/ml, p<0.05) was elevated in RUPP rats vs. NP rats and was normalized in RUPP + 7AA rats (86±9 pg/ml, p<0.05). There was a 4 fold increase in PPE in RUPP (n=7) vs. NP (n=6) rats which was reduced 2 fold in RUPP + 7AA (n=7) (p<0.05). There was no difference in GFR or plasma creatinine among the groups. Activated cytolytic placental NK cells was increased in RUPP vs. NP (8.29±1.73% vs. 2.05±1.56%, p<0.05), and was normal in RUPP +7AA (2.78±0.95%, p<0.05). Nitrate and nitrite (NOx), was decreased in RUPP vs. NP (14.0± 1.5 vs. 20.0± 1.0 μM NO 3 , p<0.05) and was improved to 18.3± 1.6 μM NO 3 in RUPP + 7AA (ns). Circulating isoprostanes were elevated for RUPP vs. NP (20.1 ± 6.3 vs. 2.8 ± 1.4 ng/mL, p< 0.05) and was normalized with RUPP + 7AA peptide treated rats (4.3 ± 2.2 ng/mL). Conclusion Inhibition of AT1‐AA from binding to the AT1R improves many PE characteristics observed in RUPP rats, thus indicating that this may be a potential therapy to further explore for PE patients. Support or Funding Information Research Supported by T32HL105324 and RO1HD067541