Angiotensin-Converting Enzyme 2 (ACE2) and ACE Activities Display Tissue-Specific Sensitivity to Undernutrition-Programmed Hypertension in the Adult Rat

Rivière, Guillaume; Michaud, Annie; Breton, Christophe; VanCamp, Gilles; Laborie, Christine; Enache, Mihaela; Lésage, Jean; Deloof, Sylvie; Corvol, Pierre; Vieau, Didier

doi:10.1161/01.hyp.0000185148.27901.fe

Cited by 109 publications

(107 citation statements)

References 41 publications

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“…51 Previous studies have demonstrated an activation of the renin-angiotensin system in MUN offspring. 52 Furthermore, the adrenal expression of angiotensin receptor 1b is increased in these offspring, 53 suggesting increased responsiveness of the adrenal to circulating angiotensin II. Elevated angiotensin II levels and increased responsiveness to its effects in MUN offspring would be expected to stimulate the expression of CYP11A1 mRNA as demonstrated by our data.…”

Section: Discussionmentioning

confidence: 94%

Maternal Undernutrition Programs Offspring Adrenal Expression of Steroidogenic Enzymes

et al. 2011

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The aim of this study was to determine the influence of maternal undernutrition (MUN) on maternal and offspring adrenal steoridogenic enzymes. Pregnant Sprague-Dawley rats were 50% food-restricted from day 10 of gestation until delivery. Control animals received ad libitum food. Offspring were killed on day 1 of life (P1) and at 9 months. We determined the messenger RNA (mRNA) expression of steroidogneic enzymes by real-time reverse transcriptase polymerized chain reaction (RT-PCR). Maternal undernutrition inhibited maternal adrenal expression of P450 cholesterol side-chain cleavage enzyme (CYP11A1), 11 betahydroxylase (CYP11B1), aldosterone synthase (CYP11B2), and adrenocorticotropic hormone (ACTH) receptor (ACTH-R; MC2 gene) compared with control offspring. There was a marked downregulation in the expression of CYP11B1, CYP11B2, 11 b-hydroxysteroid dehydrogenase type 1 and 2 (HSD1 and HSD2), CYP11A1, ACTH receptor, steroidogenic acute regulatory protein (STAR), and mineralocorticoid receptor (MCR; NR3C2 gene) mRNA in P1 MUN offspring (both genders), with no changes in glucocorticoid receptor (GCR). Quantitative immunohistochemical analysis confirmed the PCR data for GCR and MCR in P1 offspring and demonstrated lower expression of leptin receptor protein (Ob-Ra/Ob-Rb) and mRNA in P1 MUN offspring. In 9-month adult male MUN offspring, the expression of HSD1, CYP11A1, CYP11B2, Ob-Ra/Ob-Rb, and GCR mRNA were significantly upregulated with a trend toward an increase in ACTH-R and a decrease in 17 alpha-hydroxylase (CYP17A1) expression. In adult female MUN offspring, similar to males, the expression of CYP11A1, ACTH-R, and Ob-Rb mRNA were increased, whereas GCR and CYP17A1 mRNA were decreased. These results indicate that the adrenal gland is a target of nutritional programming. In utero undernutrition has a global suppressive effect on maternal and P1 offspring adrenal steroidogenic enzymes in association with reduced circulating corticosterone levels in P1 offspring, which may be secondary to a negative feedback from elevated maternal GC levels and or leptin levels in MUN dams. Gender-specific differences in steroidogenic enzyme expression were found in adult MUN offspring. The common finding of increased ACTH receptor expression in MUN adults of both genders suggests an increased sensitivity of these offspring to stress. Keywords adrenal, steroidogenesis, STAR protein, leptin receptor, ACTH receptor, maternal undernutrition, glucocorticoids, fetal programming An adverse intrauterine environment induces fetal growth restriction and is associated with development of metabolic syndrome in adult life. 1 These adverse intrauterine conditions are associated with maternal stress leading to excess glucocorticoid production which has significant impact on the fetus in terms of growth and later development of adult diseases. 2,3 Several studies have shown hyperactivity of offspring hypothalamic-pituitary-adrenal axis caused by maternal undernutrition. 4,5 Most of these studies have focused primarily on characterizat...

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Section: Discussionmentioning

confidence: 94%

Maternal Undernutrition Programs Offspring Adrenal Expression of Steroidogenic Enzymes

et al. 2011

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“…These studies confirmed that impaired fetal development has long-term metabolic consequences, sensitizing the offspring to hyperphagia and obesity, particularly when they are fed a hypercaloric diet (22,26,53), reduced leptin and insulin sensitivity (10,26,50,51), type 2 diabetes (43), and elevated blood pressure (32,44). In adults, the pivotal role of the hypothalamus, especially the arcuate nucleus (Arc), in the maintenance of energy homeostasis controlling the nutritional status and energy storage level is well established (45).…”

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confidence: 76%

“…Using a model of prenatal maternal 70% food-restricted diet (FR30) in rats throughout gestation, we previously showed that FR30 induces IUGR and programs some metabolic syndrome features in adult male rat offspring (44). We hypothesized that prenatal maternal FR30 induces developmental programming that durably modifies levels of key circulating factors acting on the hypothalamus, as well as hypothalamic gene expression, in adult offspring.…”

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confidence: 99%

Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring

Breton¹,

Lukaszewski²,

Risold³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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demiological studies suggest that maternal undernutrition predisposes the offspring to development of energy balance metabolic pathologies in adulthood. Using a model of a prenatal maternal 70% foodrestricted diet (FR30) in rats, we evaluated peripheral parameters involved in nutritional regulation, as well as the hypothalamic appetite-regulatory system, in nonfasted and 48-h-fasted adult offspring. Despite comparable glycemia in both groups, mild glucose intolerance, with a defect in glucose-induced insulin secretion, was observed in FR30 animals. They also exhibited hyperleptinemia, despite similar visible fat deposits. Using semiquantitative RT-PCR, we observed no basal difference of hypothalamic proopiomelanocortin (POMC) and neuropeptide Y (NPY) gene expression, but a decrease of the OB-Rb and an increase of insulin receptor mRNA levels, in FR30 animals. These animals also exhibited basal hypercorticosteronemia and a blunted increase of corticosterone in fasted compared with control animals. After fasting, FR30 animals showed no marked reduction of POMC mRNA levels or intensity of ␤-endorphin-immunoreactive fiber projections. By contrast, NPY gene expression and immunoreactive fiber intensity increased. FR30 rats also displayed subtle alterations of food intake: body weight-related food intake was higher and light-dark phase rhythm and refeeding time course were modified after fasting. At rest, in the morning, hyperinsulinemia and a striking increase in the number of c-Fos-containing cells in the arcuate nucleus were observed. About 30% of the c-Fos-expressing cells were POMC neurons. Our data suggest that maternal undernutrition differently programs the long-term appetite-regulatory system of offspring, especially the response of POMC neurons to energy status and food intake rhythm. maternal undernutrition; appetite programming; hypothalamus; arcuate nucleus; feeding rhythm IN ADDITION TO LIFESTYLE and dietary factors, increasing evidence suggests that the origin of some metabolic disorders that manifest in adult life may be traced to development. Indeed, epidemiological studies have shown that adverse environmental factors leading to intrauterine growth retardation (IUGR) and low birth weight may predispose individuals to later onset of energy balance metabolic pathology development (9,17,18,20,29). This has led to the concept of the developmental origin of adult diseases, also called "fetal programming," or the Barker hypothesis (4). As illustrated by the Dutch Famine Study, offspring of women exposed to famine during early pregnancy displayed an increased risk of adiposity and glucose intolerance, as well as hypertension, later in life (41).To obtain insights into the underlying mechanisms, numerous animal models, including maternal undernutrition, have been developed to promote intrauterine fetal programming (47,56). These studies confirmed that impaired fetal development has long-term metabolic consequences, sensitizing the offspring to hyperphagia and obesity, particularly when they are fed a hyperca...

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“…10,15,16 In experimental studies, first, in knockout mice lacking the ACE2 gene, blood pressure is either normal or only mildly increased compared with control littermates. 5,9,17 In rats, Pendergrass et al 18 found that hypertensive male mRen2.Lewis rats had lower cortical ACE2 activity than normotensive Lewis rats, but no difference in ACE2 activity was present between female hypertensive and normotensive rats in the same study.…”

Section: Controlsmentioning

confidence: 99%

Renal ACE2 expression and activity is unaltered during established hypertension in adult SHRSP and TGR(mREN2)27

et al. 2009

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Differential renal expression of a homolog of the angiotensin-converting enzyme (ACE), that is, ACE2, has been implicated as a genetic basis of polygenetic hypertension in the stroke-prone spontaneously hypertensive rat model. However, data on the role of ACE2 in hypertension are still inconclusive. Therefore, we analyzed kidney ACE2 mRNA, ACE2 protein and ACE2 enzyme activities in the adult polygenetic stroke-prone spontaneously hypertensive rat (SHRSP) and the monogenetic TGR(mREN2)27 rat models, in comparison with their normotensive reference strains, Wistar-Kyoto (WKY) and Spraque-Dawley (SD) rats, respectively. Kidney ACE2 mRNA was studied using quantitative real-time reverse transcriptase-PCR (RT-PCR) in cortex and medulla, whereas protein expression was scored semiquantitatively in detail in different renal structures using immunohistochemistry. Furthermore, total renal tissue ACE2 activity was measured using a fluorimetric assay that was specified by the ACE2 inhibitor DX600. In SHRSP and homozygous TGR(mREN2)27 rats with established hypertension, kidney ACE2 mRNA, protein and tissue ACE2 activities were not different from their respective WKY and SD reference strain, respectively. In addition, when we looked at renal localization, we found ACE2 protein to be predominantly present in glomeruli and endothelium with weak staining in distal and negative staining in proximal tubuli. Thus, our data challenge previous work that implicates ACE2 as a candidate gene for hypertension in SHRSP by reporting a significant reduction of ACE2 in the kidneys of SHRSP. Taken together, renal ACE2 is not altered in the SHRSP and TGR(mREN2)27 genetic rat models with established hypertension.

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Angiotensin-Converting Enzyme 2 (ACE2) and ACE Activities Display Tissue-Specific Sensitivity to Undernutrition-Programmed Hypertension in the Adult Rat

Cited by 109 publications

References 41 publications

Maternal Undernutrition Programs Offspring Adrenal Expression of Steroidogenic Enzymes

Maternal Undernutrition Programs Offspring Adrenal Expression of Steroidogenic Enzymes

Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring

Renal ACE2 expression and activity is unaltered during established hypertension in adult SHRSP and TGR(mREN2)27

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