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A novel rodent model of pregnancy complications associated with genetically determined angiotensin-converting enzyme (ACE) activity.

ABSTRACT: Brown Norway (BN) and Lewis (LW) inbred rat strains harbor different angiotensin-converting enzyme ( Ace) polymorphisms that result in higher ACE activity in BN than LW rats. Thus we hypothesized that pregnant BN rats would show pregnancy complications linked to angiotensin II (AII) activity. We performed longitudinal and cross-sectional studies in pregnant LW and BN rats. We found that BN rats have significantly higher ACE activity and AII levels at prepregnancy and throughout pregnancy compared with LW rats, except at midgestation. BN placentas and maternal kidneys had significantly higher expression of AII receptor 1 (AGTR1) and lower expression of AGTR2 than the respective LW placentas and maternal kidneys. Renin-angiotensin system activation in BN rats correlated with hypertension and proteinuria at gestational days 17-21, which were resolved after delivery. In addition, BN rat pregnancies were characterized by significant fetal loss, restricted growth in surviving fetuses, decreased uteroplacental blood flows, and decreased trophoblast remodeling of uterine arteries compared with LW pregnancies. Short-term losartan treatment significantly increased uteroplacental blood flow and fetal weight and decreased maternal blood pressure (BP) and proteinuria in BN pregnancies. In contrast, losartan treatment significantly decreased uteroplacental blood flow and fetal weight but had no significant effect on maternal BP in LW pregnancies. We conclude that Ace polymorphisms play an important role in the reproductive phenotype of BN and LW rats and that BN rats are a novel model of pregnancy complications in association with genetically controlled, increased ACE activity.

SUBMITTER: Mata-Greenwood E

PROVIDER: S-EPMC6087725 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A novel rodent model of pregnancy complications associated with genetically determined angiotensin-converting enzyme (ACE) activity.

Mata-Greenwood Eugenia E Blood Arlin B AB Sands LeeAnna D LD Bragg Shannon L SL Xiao Daliao D Zhang Lubo L

American journal of physiology. Endocrinology and metabolism 20180123 1

Brown Norway (BN) and Lewis (LW) inbred rat strains harbor different angiotensin-converting enzyme ( Ace) polymorphisms that result in higher ACE activity in BN than LW rats. Thus we hypothesized that pregnant BN rats would show pregnancy complications linked to angiotensin II (AII) activity. We performed longitudinal and cross-sectional studies in pregnant LW and BN rats. We found that BN rats have significantly higher ACE activity and AII levels at prepregnancy and throughout pregnancy compare ...[more]

PMID: 29360395

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Project description:Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.

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A novel rodent model of pregnancy complications associated with genetically determined angiotensin-converting enzyme (ACE) activity.

Publications

A novel rodent model of pregnancy complications associated with genetically determined angiotensin-converting enzyme (ACE) activity.

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