Angiotensin II Type 1 Autoantibody Induced Hypertension During Pregnancy Is Associated With Renal Endothelial Dysfunction

Parrish, Marc; Ryan, Michael J.; Glover, Porter H.; Brewer, Justin; Ray, Lillian; Dechend, Ralf; Martin, James N.; LaMarca, Babbette

doi:10.1016/j.genm.2011.04.003

Cited by 48 publications

(36 citation statements)

References 20 publications

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“…VD supplementation significantly reduced renal production of ET-1 in RUPP rats in correlation with reduction of AT 1 -AA. ET-1 has been shown to mediate, at least in part, the hypertensive responses of RUPP and AT 1 -AA-infused, sFlt-1-treated, and to (19,52,62). The observed improvement of ET-1 levels suggests improved function and endothelial activation with VD supplementation, which likely resulted from reduced CD4ϩ T cells, sFlt-1 secretion, and AT 1 -AA-mediated signaling, all of which could play a role in the observed reduction of blood pressure.…”

Section: R350 Vit D Improves Pathophysiology In Preeclamptic Rat Modelmentioning

confidence: 99%

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

Faulkner

Cornelius

Amaral

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Deficiency of vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine whether VD supplementation would reduce the pathophysiology and hypertension associated with the reduced uterine perfusion pressure (RUPP) rat model of PE. Normal pregnant (NP) and RUPP rats were supplemented with VD2 or VD3 (270 IU and 15 IU/day, respectively) on gestation days 14 -18 and mean arterial pressures (MAPs) measured on day 19. MAP increased in RUPP to 123 Ϯ 2 mmHg compared with 102 Ϯ 3 mmHg in NP and decreased to 113 Ϯ 3 mmHg with VD2 and 115 Ϯ 3 mmHg with VD3 in RUPP rats. Circulating CD4ϩ T cells increased in RUPP to 7.90 Ϯ 1.36% lymphocytes compared with 2.04 Ϯ 0.67% in NP but was lowered to 0.90 Ϯ 0.19% with VD2 and 4.26 Ϯ 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 Ϯ 0.4 bpm in RUPPs to 8.3 Ϯ 0.5 bpm with VD2 and to 15.4 Ϯ 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 Ϯ 2.1-fold change from NP) and decreased with both VD2 (3.3 Ϯ 1.1-fold) and VD3 (3.1 Ϯ 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 Ϯ 6.6 pg/ml in VD2-treated and 91.0 Ϯ 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 Ϯ 19.9 pg/ml in RUPP rats. VD treatment reduced CD4ϩ T cells, AT1-AA, ET-1, sFlt-1, and blood pressure in the RUPP rat model of PE and could be an avenue to improve treatment of hypertension in response to placental ischemia. hypertension; immune activation; preeclampsia; vitamin D PREECLAMPSIA (PE) IS A CLINICAL condition occurring in up to 7% of pregnancies in the United States commonly manifesting in late gestation (Ͼ20 wk gestation) with hypertension, placental ischemia, and low birth weight (5,27,47,48,58). Current treatment strategies for preeclampsia are targeted at safely lowering blood pressure and alleviating maternal complications (5, 48). PE pregnancies are characterized by an abnormal immune profile compared with that seen in normal pregnancies. PE women exhibit an altered immune balance favoring proinflammatory factors, such as CD4ϩ T cells, B cells, inflammatory cytokines, and autoantibodies to the angiotensin type 1 receptor (AT 1 -AA), which are known to stimulate production of antiangiogenic protein-soluble FMS-like tyrosine kinase-1 (sFlt-1) (18,33,34,56,57). In contrast, anti-inflammatory T regulatory cells (TREGs) are decreased in PE (22,53,56). These immune alterations are recapitulated in the established experimental model of PE, the reduced uterine perfusion pressure (RUPP) rat (1,20,21). Adoptive transfer of CD4ϩ T cells from RUPP rats induces hypertension, AT 1 -AA, inflammatory cytokines and sFlt-1, and endothelin-1 (ET-1) in normal pregnant rats, indicating the significant role these cells play in the pathogenesis of this disease (63). Furthermore, AT 1 -AA and sFlt-1 play a significant role in the development of endothelial dysfunction and hyp...

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Section: R350 Vit D Improves Pathophysiology In Preeclamptic Rat Modelmentioning

confidence: 99%

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

Faulkner

Cornelius

Amaral

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

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“…The AT 1-AA activity was measured using spontaneously beating neonatal rat cardiomyocytes and characterized and antagonized specifically using AT1 receptor antagonists. The results express the difference between the basal beating rate of the cardiomyocytes and the beating rate measured after the addition of the AT1-AA (increase in number of beats/min or ⌬ beats/min) (6,7,19,21,32,33). AT1-AAs were assessed in NP, RUPP controls, and RUPPϩNPTRegs rats.…”

Section: Adoptive Transfer Of Np and Rupp T Reg Cellsmentioning

confidence: 99%

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

Cornelius

Amaral

Harmon

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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The reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits much of the pathology characterizing this disease, such as hypertension, inflammation, suppressed regulatory T cells (T Regs), reactive oxygen species (ROS), and autoantibodies to the ANG II type I receptor (AT1-AA) during pregnancy. The objective of this study was to determine whether supplementation of normal pregnant (NP) TRegs into RUPP rats would attenuate the pathophysiology associated with preeclampsia during pregnancy. CD4 ϩ /CD25ϩ T cells were isolated from spleens of NP and RUPP rats, cultured, and injected into gestation day (GD) 12 normal pregnant rats that underwent the RUPP procedure on GD 14. On GD 1, mean arterial pressure (MAP) was recorded, and blood and tissues were collected for analysis. One-way ANOVA was used for statistical analysis. MAP increased from 99 Ϯ 2 mmHg in NP (n ϭ 12) to 127 Ϯ 2 mmHg in RUPP (n ϭ 21) but decreased to 118 Ϯ 2 mmHg in RUPPϩNP TRegs (n ϭ 17). Circulating IL-6 and IL-10 were not significantly changed, while circulating TNF-␣ and IL-17 were significantly decreased after supplementation of TRegs. Placental and renal ROS were 339 Ϯ 58.7 and 603 Ϯ 88.1 RLU·min Ϫ1 ·mgϪ1 in RUPP and significantly decreased to 178 Ϯ 27.8 and 171 Ϯ 55.6 RLU·min Ϫ1 ·mg Ϫ1 , respectively, in RUPPϩNP TRegs; AT1-AA was 17.81 Ϯ 1.1 beats per minute (bpm) in RUPP but was attenuated to 0.50 Ϯ 0.3 bpm with NP TRegs. This study demonstrates that NP TRegs can significantly improve inflammatory mediators, such as IL-17, TNF-␣, and AT 1-AA, which have been shown to increase blood pressure during pregnancy.hypertension; pregnancy; inflammation; oxidative stress; regulatory T cells PREECLAMPSIA IS A PREGNANCY-ASSOCIATED disorder that affects 5-8% of pregnancies and is a major cause of maternal, fetal, and neonatal morbidity and mortality (9,29,37). Hallmark characteristics of preeclampsia are new-onset hypertension after 20 wk gestation, proteinuria, chronic immune activation, fetal growth restriction, and maternal endothelial dysfunction. The pathophysiological mechanisms that lead to the development of preeclampsia are poorly understood. It is thought that poor invasion of trophoblasts leads to insufficient spiral artery remodeling, resulting in placental ischemia (4, 10, 31). The hypoxic environment that results from this placental ischemia is suggested to be an important factor in the development of oxidative stress and a shift in the balance of antiangiogenic and proangiogenic factors, which plays a role in endothelial dysfunction of the placenta and maternal vasculature (10). Previous studies from our laboratory in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia demonstrate that the total population of CD4-positive (CD4 ϩ ) T cells isolated from RUPP spleens and transferred to NP rats causes similar pathology to that seen in RUPP rats (46), demonstrating a role for this population in mediating pathophysiology in response to placental ischemia. Recent data from both clinical and animal model stud...

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“…MAP was monitored with a pressure transducer (Cobe III Transducer CDX Sema) and recorded continuously after a 1-h stabilization period. Subsequently, a blood and urine sample was collected, kidneys and placentas were harvested, and litter size and pup weights were recorded under anesthesia (9,12).…”

Section: Protocol 1a: Effect Of Il-17 Infusion On Map In Pregnant Ratsmentioning

confidence: 99%

IL-17-mediated oxidative stress is an important stimulator of AT1-AA and hypertension during pregnancy

Dhillion

Wallace

Herse³

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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., Dechend R, LaMarca B. IL-17-mediated oxidative stress is an important stimulator of AT1-AA and hypertension during pregnancy. Am J Physiol Regul Integr Comp Physiol 303: R353-R358, 2012. First published June 20, 2012 doi:10.1152/ajpregu.00051.2012.-Preeclampsia is associated with autoimmune cells TH17, secreting interleukin-17, autoantibodies activating the angiotensin II type I receptor (AT1-AA), and placental oxidative stress (ROS). The objective of our study was to determine whether chronic IL-17 increases blood pressure by stimulating ROS and AT1-AAs during pregnancy. To answer this question four groups of rats were examined: normal pregnant (NP, n ϭ 20), NPϩIL-17 (n ϭ 12), NPϩtempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) (n ϭ 7) (a superoxide dismutase mimetic that scavenges ROS), and NPϩIL-17ϩtempol (n ϭ 11). IL-17 (150 pg/day) was infused into NP rats while tempol was administered via the drinking water ad libitum. On day 19 blood pressure (MAP) was recorded, and plasma, urine, and tissue were collected for isolation of ROS detected by chemilluminescent technique. Urinary isoprostane was measured by ELISA. AT1-AAs were determined via cardiomyocyte assay and expressed as beats per minute. MAP increased from 98 Ϯ 3 mmHg in NP to 123 Ϯ 3 mmHg in IL-17-infused NP rats. Urinary isoprostane increased from 1,029 Ϯ 1 in NP to 3,526 Ϯ 2 pg·mg Ϫ1 ·day Ϫ1 in IL-17-infused rats (P Ͻ 0.05). Placental ROS was 436 Ϯ 4 RLU·ml Ϫ1 ·min Ϫ1 (n ϭ 4) in NP and 702 Ϯ 5 (n ϭ 5) RLU·ml Ϫ1 ·min Ϫ1 in IL-17-treated rats. Importantly, AT1-AA increased from 0.41 Ϯ 0.05 beats/min in NP rats (n ϭ 8) to 18.4 Ϯ 1 beats/min in IL-17 rats (n ϭ 12). Administration of tempol attenuated the hypertension (101 Ϯ 3 mmHg) ROS (459 Ϯ 5 RLU·ml Ϫ1 ·min Ϫ1 ) and blunted AT1-AAs (7.3 Ϯ 0.6 beats/min) in NPϩIL-17ϩtempol-treated rats. Additionally, AT1 receptor blockade inhibited IL-17-induced hypertension and placental oxidative stress. MAP was 105 Ϯ 5 mmHg and ROS was 418 Ϯ 5 RLU·ml

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Angiotensin II Type 1 Autoantibody Induced Hypertension During Pregnancy Is Associated With Renal Endothelial Dysfunction

Cited by 48 publications

References 20 publications

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

IL-17-mediated oxidative stress is an important stimulator of AT1-AA and hypertension during pregnancy

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