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. 2014 Aug;211(2):158.e1-6.
doi: 10.1016/j.ajog.2014.02.018. Epub 2014 Feb 15.

Progesterone supplementation attenuates hypertension and the autoantibody to the angiotensin II type I receptor in response to elevated interleukin-6 during pregnancy

Lorena M Amaral  1 , Luissa Kiprono  2 , Denise C Cornelius  1 , Carrie Shoemaker  1 , Kedra Wallace  3 , Janae Moseley  1 , Gerd Wallukat  4 , James N Martin Jr  2 , Ralf Dechend  4 , Babbette LaMarca  5
Affiliations

Progesterone supplementation attenuates hypertension and the autoantibody to the angiotensin II type I receptor in response to elevated interleukin-6 during pregnancy

Lorena M Amaral et al. Am J Obstet Gynecol. 2014 Aug.

Abstract

Objective: Preeclampsia is a multisystem disorder recognized as hypertension with proteinuria developing >20 weeks' gestation. Preeclampsia is associated with chronic immune activation characterized by increased T and B lymphocytes, cytokines, and antibodies activating the angiotensin II type I receptor (AT1-AA). Hypertension in response to elevated interleukin (IL)-6 during pregnancy occurs with increased renin activity and AT1-AA, and reduced kidney function.

Study design: We aim to determine whether 17-alpha-hydroxyprogesterone caproate (17-OHPC), progesterone, improved inflammatory pathways during elevated IL-6 in pregnant rats. IL-6 (5 ng/d) was infused via miniosmotic pumps into normal pregnant (NP) rats beginning on day 14 of gestation and 17-OHPC (3.32 mg/kg) was diluted in normal saline and injected on day 18. Blood pressure (mean arterial pressure [MAP]) determination and serum collection were performed on day 19 of gestation.

Results: MAP in NP was 100 ± 3 mm Hg, which increased with IL-6 to 112 ± 4 mm Hg (P < .05). Pregnant rats given 17-OHPC alone had a MAP of 99 ± 3 mm Hg and MAP increased to 103 ± 2 mm Hg in IL-6+17-OHPC. AT1-AA was 1.2 ± 0.5 bpm in NP rats, increased to 17 ± 9 bpm with IL-6 infusion but administration of 17-OHPC significantly blunted AT1-AA to 4 ± 0.8 bpm in NP+IL-6+17-OHPC. Total circulating nitrate/nitrite was significantly decreased and placental Ser(1177)-phosporylated-eNOS/eNOS was lowered with IL-6 infusion. Supplementation of 17-OHPC significantly improved placental Ser(1177)-phosporylated-eNOS/eNOS however, circulating nitrate/nitrite was unchanged with 17-OHPC supplementation.

Conclusion: This study illustrates that 17-OHPC attenuated hypertension, decreased AT1-AA activity, and improved placental nitric oxide in response to elevated IL-6 during pregnancy and could lend hope to a new potential therapeutic for preeclampsia.

Keywords: cytokines; hypertension; inflammation; nitric oxide; pregnancy; progesterone; renin angiotensin system.

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Conflict of interest statement

The authors report no conflict of interest.

Figures

FIGURE 1
FIGURE 1. Supplementation of 17-OHPC blunts hypertension in response to elevated IL-6 during pregnancy
Data are shown as means ± SEM (n = 6–10/group). IL, interleukin; MAP, mean arterial pressure; 17-OHPC, 17-alpha-hydroxyprogesterone caproate. *P < .05 vs normal pregnant (NP) group; #P < .05 vs NP6 group. Amaral. Progesterone effects on IL-6-induced hypertension. Am J Obstet Gynecol 2014.
FIGURE 2
FIGURE 2. Supplementation of 17-OHPC decreased activity of AT1-AA in response to elevated IL-6 during pregnancy
Data are shown as means ± SEM (n = 4–6/group). IL, interleukin; 17-OHPC, 17-alpha-hydroxyprogesterone caproate. *P < .05 vs normal pregnant (NP) group; #P < .05 vs NP6 group. Amaral. Progesterone effects on IL-6-induced hypertension. Am J Obstet Gynecol 2014.
FIGURE 3
FIGURE 3. Placental protein expression of eNOS and Ser1177-P-eNOS in IL-6-induced hypertension rats
NOS protein expression was determined by Western blot analysis as described in “Materials and Methods” section. A, Representative Western blots showing eNOS and Ser1177-P-eNOS expression in the placentas from rats. B, Bar graph showing the densitometric data. β-Actin content was used for normalization to both gels. Data are shown as means ± SEM (n = 4–6/group). Arrow indicates the band of interest. IL, interleukin; OHP, alpha-hydroxyprogesterone caproate; Ser1177-P-eNOS, phosporylated. *P < .05 vs normal pregnant (NP) group. #P < .05 vs NP6 group. Amaral. Progesterone effects on IL-6-induced hypertension. Am J Obstet Gynecol 2014.
FIGURE 4
FIGURE 4. Total circulating nitrate/nitrite is reduced in IL-6-induced hypertension
Nitrate/nitrite was determined via enzyme-linked immunosorbent assay and data are shown as ± SEM (n = 4–6/group). There was no difference when 17-alpha-hydroxyprogesterone caproate (OHPC) was administered to pregnant rats. IL, interleukin. *P < .05 vs normal pregnant (NP) group. Amaral. Progesterone effects on IL-6-induced hypertension. Am J Obstet Gynecol 2014.
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