Short-term suppression of the renin-angiotensin system in mice associated with hypertension during pregnancy

Ishimaru, Tomohiro; Ishida, Junji; Nakamura, Shoko; Hashimoto, Misuzu; Matsukura, Tanomu; Nakamura, Ayumi; Kunita, Satoshi; Sugiyama, Fumihiro; Yagami, Ken‐ichi; Fukamizu, Akiyoshi

doi:10.3892/mmr.2012.886

Cited by 5 publications

(4 citation statements)

References 32 publications

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“…There was also a slight reduction in the overall risk of developing proteinuria/PE when beta blockers and calcium channel blockers considered together (but not alone) were compared with methyldopa (1230). In mice, olmesartan (together with captopril) proved usefully anti-hypertensive (1234); this is of interest because olmesartan is also an agonist of the vitamin D receptor (1235). However, it was not mentioned in either Ref.…”

Section: Prevention Strategiesmentioning

confidence: 99%

A Dormant Microbial Component in the Development of Preeclampsia

Kell

Kenny

2016

Front. Med.

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Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “preeclampsia” that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.

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Section: Prevention Strategiesmentioning

confidence: 99%

A Dormant Microbial Component in the Development of Preeclampsia

Kell

Kenny

2016

Front. Med.

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“…2008; Ishimaru et al. 2012), SBP of PAH mice started to increase at day 13 of pregnancy (P13) and was significantly higher than that of WT mice during late pregnancy (Fig. 1).…”

Section: Resultsmentioning

confidence: 91%

“…2008; Ishimaru et al. 2012). SBP measurement was performed in the morning of P1, P3, P6, P9, and from P12 to P19.…”

Section: Methodsmentioning

confidence: 99%

Angiotensin II accelerates mammary gland development independently of high blood pressure in pregnancy-associated hypertensive mice

et al. 2015

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Angiotensin II (AngII) is a vasopressor hormone that has critical roles in maintenance of normal blood pressure and pathogenesis of cardiovascular diseases. We previously generated pregnancy-associated hypertensive (PAH) mice by mating female human angiotensinogen transgenic mice with male human renin transgenic mice. PAH mice exhibit hypertension in late pregnancy by overproducing AngII. A recent study demonstrated that angiotensin II type I (AT1) receptor is expressed in mammary epithelial cells and its signaling is critical for mammary gland involution after weaning. However, the role of AngII-AT1 receptor signaling in the development of mammary gland during pregnancy remains unclear. In this study, to investigate the role of AngII-AT1 receptor signaling in mammary gland development during pregnancy, we analyzed the mammary gland of PAH mice. Histological and gene expression analyses revealed that lobuloalveolar development was accelerated with increased milk protein production and lipid accumulation in the mammary gland of PAH mice. Furthermore, AT1 receptor blocker treatment suppressed acceleration of mammary gland development in PAH mice, while the treatment of hydralazine, another antihypertensive drug, did not. These data suggest that AngII-AT1 receptor-induced signaling accelerates mammary gland development during pregnancy through hypertension-independent mechanism.

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“…Our results also show that pregnant women carrying the TT genotype of the AGT gene are more at risk for development of PE. This is possibly because RAS in the local tissue can also generate angiotensin in addition to the classic circulation system [16]. The AGT gene, as part of the uterine spiral artery RAS, may be involved in spiral artery remodeling [17].…”

Section: Discussionmentioning

confidence: 99%

Association of Angiotensinogen Gene Polymorphisms and Angiogenic Factors with Preeclampsia in Chinese Women

Song¹,

Shou-zhen²,

Wang³

et al. 2013

Gynecol Obstet Invest

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Objective: To investigate the association of angiotensinogen (AGT) gene polymorphisms and angiogenic factors with preeclampsia (PE) in Chinese women. Methods: A study on Chinese women was performed. Detection of the M235T polymorphism of AGT gene was carried out by PCR. Using a χ² test, genotype and allele frequencies were compared in all groups. Maternal serum levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt1) at gestation were compared between 92 women with PE and 100 controls by ELISA. Results: Compared to the controls, the AGT homozygous of TT genotype in PE occurred significantly more frequently and the T allele was observed to occur more frequently than the M allele (p < 0.05). sFlt1 was present in high quantities in the serum of women with PE and was associated with low levels of free VEGF and PlGF (p < 0.05). Plasma sFlt1 levels are higher in PE patients with TT heterozygotes compared with MM homozygotes, but PIGF is lower (p < 0.05). Plasma VEGF concentrations showed no significant difference. Conclusions: Our study showed that AGT M235T polymorphism is associated with PE in Chinese women. Furthermore, the gene polymorphism of the components of the renin-angiotensin system may contribute to the concentration alterations of sFlt1, VEGF, and PlGF in maternal serum, which causes disordered vasculogenesis contributing to PE.

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Short-term suppression of the renin-angiotensin system in mice associated with hypertension during pregnancy

Cited by 5 publications

References 32 publications

A Dormant Microbial Component in the Development of Preeclampsia

A Dormant Microbial Component in the Development of Preeclampsia

Angiotensin II accelerates mammary gland development independently of high blood pressure in pregnancy-associated hypertensive mice

Association of Angiotensinogen Gene Polymorphisms and Angiogenic Factors with Preeclampsia in Chinese Women

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