Transgenic mice for studies of the renin–angiotensin system in hypertension

Lavoie, Julie L.; Bianco, Robert A.; Sakai, Koji; Keen, Henry L.; Ryan, Michael J.

doi:10.1111/j.1365-201x.2004.01332.x

Cited by 25 publications

(28 citation statements)

References 59 publications

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“…21 For instance, it has been shown that endothelial dysfunction is present and that increased oxidative stress in this model also contributed to the vascular dysfunction. 38 We can, thus, hypothesize that endothelial dysfunction may also be present in the female R ϩ A ϩ mice and may, therefore, contribute to the development of SPE symptoms in this model.…”

Section: Male Rmentioning

confidence: 99%

“…[17][18][19][20] Indeed, male mice have elevated blood pressure, Ϸ150 mm Hg, 17 and show high plasma levels of Ang II with evidence of end-organ damage, such as endothelial dysfunction. 21 Although these phenotypes have not been characterized in females, they should be similar, because transgene expression is equivalent. Therefore, because chronic hypertension is an important risk factor for PE, 22 we hypothesized that hypertensive R ϩ A ϩ double-transgenic female mice would develop SPE, and, therefore, we propose these mice as an animal model of this clinical reality.…”

mentioning

confidence: 99%

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Mice Overexpressing Both Human Angiotensinogen and Human Renin as a Model of Superimposed Preeclampsia on Chronic Hypertension

et al. 2009

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Abstract-Preeclampsia is the major cause of maternal and fetal mortality/morbidity. Because hypertension is an important risk factor for preeclampsia, we investigated whether hypertensive mice that overexpress human renin and angiotensinogen develop superimposed preeclampsia. Given that the mechanisms underlying this disease are still poorly understood, animal models are of great use for elucidatation. Blood pressure and proteinuria were measured by telemetry and ELISA, respectively. Heart function was evaluated by echocardiography, whereas pathological cardiac hypertrophy-related genes were assessed by real-time PCR. Soluble fms-like tyrosine kinase 1 plasma concentrations were quantitated by ELISA and placental expression by real-time PCR. Transgenic mice develop de novo proteinuria during gestation and marked blood pressure elevation, which are hallmarks of superimposed preeclampsia on chronic hypertension. Abnormal placentation present in these mothers produced a significant decrease in pup and placental weight and was associated with an increased placental expression of soluble fms-like tyrosine kinase 1. We also found heightened circulating levels of this receptor, when adjusted for placental mass, as has been observed in women who suffer from preeclampsia. Cardiac hypertrophy could be observed in the transgenic mice and was exacerbated by gestation. As a result, heart function was significantly decreased, and markers of pathological hypertrophy were increased. Our data, thus, confirm the characterization of a new model of superimposed preeclampsia on chronic hypertension. Because chronically hypertensive women are at risk of developing the pathology, our model reflects a clinical reality and is, thus, an excellent tool to elucidate the molecular mechanisms triggering this disease. Key Words: preeclampsia Ⅲ mouse model Ⅲ renin-angiotensin system Ⅲ cardiac hypertrophy Ⅲ hypertension P reeclampsia (PE) has been studied extensively in the last 2 decades, because it is the most common cause of fetal and maternal mortality and morbidity. 1 However, thus far, apart from delivery, there are no available treatments, because antihypertensive medications are deleterious to the fetus. 2 This human pregnancy-associated syndrome is characterized by the new occurrence of proteinuria and hypertension, in previously normotensive women, or a progression of chronic hypertension to superimposed PE (SPE). 3 Other symptoms that can also be associated with this disease are placental pathology and cardiac hypertrophy. 1,4 Because it is difficult to predict disease onset, studies in humans are challenging and require a tremendous number of subjects to be of any significance. Moreover, few animal models develop PE spontaneously. [5][6][7] Because it has been suggested that PE may not be a homogenous disease, similar to essential hypertension, many different animal models may be required to characterize the different faces of this pathology that is still so poorly understood.The renin-angiotensin system (RAS) is postulated to be ...

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Section: Male Rmentioning

confidence: 99%

mentioning

confidence: 99%

Mice Overexpressing Both Human Angiotensinogen and Human Renin as a Model of Superimposed Preeclampsia on Chronic Hypertension

et al. 2009

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“…Although the compensatory hyperinsulinemia that results from IR temporarily delays the development of diabetes, as demonstrated in rat studies, it has other effects that may ultimately increase blood pressure (BP) [4]. Hyperinsulinemia promotes reabsorption of sodium and water in proximal renal tubules, leading to volume expansion and BP increase [4], which may amplify SNS activity [12] and may activate the RAAS [21,22]. However, there is no direct experimental evidence suggesting that corrections in these defects of insulin action will decrease BP; this remains a challenge for the clinician/researcher to prove "cause and effect".…”

Section: Compensatory Hyperinsulinemiamentioning

confidence: 99%

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

Hayden

Sowers

2008

Journal of the American Society of Hypertension

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Hypertension, a multifactorial-polygenic disease, interacts with multiple environmental stressors and results in functional and structural changes in numerous end organs, including the cardiovascular system. This can result in coronary heart disease, stroke, peripheral vascular disease, congestive heart failure, end-stage renal disease, insulin resistance, and damage to the pancreatic islet. Hypertension is the most important modifiable risk factor for major health problems encountered in clinical practice. Whereas hypertension was once thought to be a medical condition based on discrete blood pressure readings, a new concept has emerged defining hypertension as part of a complex and progressive metabolic and cardiovascular disease, an important part of a cardiometabolic syndrome. The central role of insulin resistance, oxidative stress, endothelial dysfunction, metabolic signaling defects within tissues, and the role of enhanced tissue renin-angiotensin-aldosterone system activity as it relates to hypertension and type 2 diabetes mellitus is emphasized. Additionally, this review focuses on the effect of hypertension on functional and structural changes associated with the vulnerable pancreatic islet. Various classes of antihypertensive drugs are reviewed, especially their roles in delaying or preventing damage to the vulnerable pancreatic islet, and thus delaying the development of type 2 diabetes mellitus.

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“…81 Evidence supports that local Ang II synthesis occurs in select tissues. [82][83][84][85] Tissues expressing all or most of the components of a local RAS include the heart, smooth muscle vasculature cells, kidney, brain, adrenal gland, pancreas, placenta, testes and adipose tissue. Overexpressing RAS genes in animals and RAS knockout models have allowed investigators to detail the presence and function of a local RAS in a variety of tissues.…”

Section: Effects Of Local Renin-angiotensin System I Presence Of Locmentioning

confidence: 99%

“…Overexpressing RAS genes in animals and RAS knockout models have allowed investigators to detail the presence and function of a local RAS in a variety of tissues. [82][83][84][86][87][88] Local RAS primarily exerts autocrine and paracrine actions via Ang II activation of the tissue-specific Ang II type 1 receptor. 89 It also interacts with the endocrine RAS and other peptides on multiple levels.…”

Section: Effects Of Local Renin-angiotensin System I Presence Of Locmentioning

confidence: 99%

Angiotensin II receptor blockade and insulin sensitivity in overweight and obese adults with elevated blood pressure

Marinik

Frisard

Hulver

et al. 2013

Therapeutic Advances in Cardiovascular Disease

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Currently, it is reported that ~65% and 34% of the U.S. population is overweight and obese, respectively. Obesity is a major risk factor for cardiovascular disease. Overweight and obese individuals are also at an increased risk of developing hypertension. Whole-body insulin sensitivity is reduced in obesity, resulting in insulin resistance and increased risk of type 2 diabetes. One possible mechanism contributing to insulin resistance in obesity hypertension is renin-angiotensin system (RAS) overactivation. The RAS exhibits vasocontricting and sodiumretaining properties, yet in vivo and in vitro animal experiments suggest impairment of wholebody insulin sensitivity with increased angiotensin II (Ang II) exposure. Furthermore, evidence from clinical studies indicates Ang II receptor blockers (ARBs) may reduce the incidence of new-onset diabetes compared to other antihypertensive agents in at-risk hypertensive patients.However, it is unclear if whole-body insulin sensitivity is improved with Ang II receptor blockade in humans. Thus, we tested the hypothesis that 8-week Ang II receptor blockade with olmesartan would improve whole-body insulin sensitivity in overweight and obese individuals with elevated blood pressure (BP). Olmesartan was selected for the present study because it is devoid of partial PPARγ agonist activity. To test our hypothesis, intravenous glucose tolerance tests were performed to measure insulin sensitivity before and after control and ARB treatment in a randomized crossover manner. Because skeletal muscle tissue accounts for ~75-90% of insulin-stimulated glucose uptake, a secondary exploratory aim was to examine skeletal muscle inflammatory and collagen response in relation to insulin sensitivity during ARB treatment. No baseline differences were observed between treatments (P>0.05). Both systolic (-11.7

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Transgenic mice for studies of the renin–angiotensin system in hypertension

Cited by 25 publications

References 59 publications

Mice Overexpressing Both Human Angiotensinogen and Human Renin as a Model of Superimposed Preeclampsia on Chronic Hypertension

Mice Overexpressing Both Human Angiotensinogen and Human Renin as a Model of Superimposed Preeclampsia on Chronic Hypertension

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

Angiotensin II receptor blockade and insulin sensitivity in overweight and obese adults with elevated blood pressure

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