The importance of m6A topology in chicken embryo mRNA: a precise mapping of m6A at the conserved chicken ß-actin zipcode.

N6-methyladenosine (m6A) in mRNA regulates almost every stage in the mRNA life cycle, and the development of methodologies for the high-throughput detection of methylated sites in mRNA using m6A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIPSeq) or m6A individual-nucleotide-resolution cross-linking and immunoprecipitation (miCLIP) have revolutionized the m6A research field. Both of these methods are based on immunoprecipitation of fragmented mRNA. However, it is well documented that antibodies often have nonspecific activities, thus verification of identified m6A sites using an antibody-independent method would be highly desirable. We mapped and quantified the m6A site in the chicken ß-actin zipcode based on the data from chicken embryo MeRIPSeq results and our RNA-Epimodification Detection and Base-Recognition (RedBaron) antibody-independent assay. We also demonstrated that methylation of this site in the ß-actin zipcode enhances ZBP1 binding in vitro, while methylation of a nearby adenosine abolishes binding. This suggests that m6A may play a role in regulating localized translation of ß-actin mRNA, and the ability of m6A to enhance or inhibit a reader protein's RNA binding highlights the importance of m6A detection at nucleotide resolution.

Salivary iodide status as a measure of whole body iodine homoeostasis?

Iodine is a trace element required to produce the thyroid hormones, which are critical for development, growth and metabolism. To ensure appropriate population iodine nutrition, convenient and accurate methods of monitoring are necessary. Current methods for determining iodine status either involve a significant participant burden or are subject to considerable intra-individual variation. The continuous secretion of iodide in saliva potentially permits its use as a convenient, non-invasive assessment of status in populations. To assess its likely effectiveness, we reviewed studies analysing the association between salivary iodide concentration (SIC) and dietary iodine intake, urinary iodide concentration (UIC) and/or 24-h urinary iodide excretion (UIE). Eight studies conducted in different countries met the inclusion criteria, including data for 921 subjects: 702 healthy participants and 219 with health conditions. SIC correlated positively with UIC and/or UIE in four studies, with the strength of relationship ranging from r = 0·19 to r = 0·90 depending on sampling protocol, age, and if salivary values were corrected for protein concentration. Additionally, SIC positively correlated with dietary intake, being strongest when saliva was collected after dinner. SIC varied with external factors, including thyroid function, use of some medications, smoking and overall health status. Evidence provided here supports the use of SIC as a viable, low-burden method for determining iodine status in populations. However, small sample sizes and high variability indicates the need for more extensive analyses across age groups, ethnicities, disease states and dietary groups to clarify the relative accuracy and reliability in each case and standardise procedure.

Impact of lifestyle factors on dietary vitamin B6 intake and plasma pyridoxal 5'-phosphate level in UK adults: National Diet and Nutrition Survey Rolling Programme (NDNS) (2008-2017).

Reduction in dietary vitamin B6 intake is associated with an increased relative risk of diseases such as cancer, atherosclerosis and cognitive dysfunction. The current research has assessed vitamin B6 intakes and PLP concentrations as a marker of vitamin B6 status among the UK adult (≥ 19 years) population. This study was carried out using a cross-sectional analysis of the National Diet and Nutrition Survey Rolling Programme (NDNS) (2008-2017). The impacts of lifestyle factors, including type of diet, smoking, alcohol consumption, and commonly used medications grouped by therapeutic usage, were determined, and data were analysed using IBM SPSS®. Results are expressed as medians (25th-75th percentiles), with P values ≤ 0·05 considered statistically significant. Among UK adults, the median intakes of total population of dietary vitamin B6 met the reference nutrient intake and median plasma PLP concentrations were above the cut-off of vitamin B6 deficiency; however, we found an association between reduction in vitamin B6 intake and plasma PLP concentration and age group (P < 0·001). Smokers had significantly lower plasma PLP concentrations than non-smokers (P < 0·001). Moreover, regression analysis showed some commonly used medications were associated with plasma PLP levels reduction (P < 0·05). Taken together, we report on a tendency for dietary vitamin B6 intake and plasma PLP concentrations to decrease with age and lifestyle factors such as smoking and medication usage. This information could have important implications for smokers and in the elderly population using multiple medications (polypharmacy).

Systematic review and meta-analysis of iodine nutrition in modern vegan and vegetarian diets.

Vegan and vegetarian diets are widely supported and adopted, but individuals following such diets remain at greater risk of iodine deficiency. This systematic review and meta-analysis was conducted to assess the iodine intake and status in adults following a vegan or vegetarian diet in the modern day. A systematic review and quality assessment were conducted from October 2020 to December 2022 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidance. Studies were identified in Ovid MEDLINE, Web of Science, PubMed, and Scopus. Eleven articles were eligible for review containing 4421 adults (aged ≥ 18 years). Vegan groups had the lowest median urinary iodine concentration (mUIC) (12·2/l). None of the dietary groups had mUIC within the optimal range for iodine status (100-200 µg/l) (WHO). Vegan diets had the poorest iodine intake (17·3 µg/d) and were strongly associated with lower iodine intake (P = < 0·001) compared with omnivorous diets. Lower intake in vegan diets was influenced by sex (P = 0·007), the presence of voluntary or absence of Universal Salt Iodisation (USI) programmes (P = 0·01 & P = < 0·001), and living in a country with adequate iodine nutrition (P = < 0·001). Vegetarians and particularly vegans living in countries with no current USI programme continue to have increased risk of low iodine status, iodine deficiency and inadequate iodine intake. Further research into the usefulness of mandatory fortification of vegan appropriate foods is required.

Influence of income on diet quality and daily iron and zinc intake: analysis of the National Diet and Nutrition Survey of British females aged 11-14 and 15-18 years.

PURPOSE: A negative socio-economic gradient exists for diet and health outcomes. Since cheaper diets are associated with increased energy and lower nutrient density, we investigated the influence of income on iron and zinc intakes and overall diet quality for adolescent (DQI-A) females aged 11-18 years. METHODS: National Diet and Nutrition Survey (NDNS years 7 and 8) data for iron and zinc intake and overall diet quality was assessed by household income quintile across females aged 11-18 years. RESULTS: Equivalised household income positively correlated with Diet quality index for adolescents (DQI-A) (P < 0.001) Females aged 15-18 years in income quintiles (IQs) I and 2, had a greater proportion of respondents with low to intermediate DQI-A score compared to higher IQs (P = 0.002). NDNS data showed intake was negatively influenced by income amongst females aged 11-14 years for iron (P = 0.009) and zinc (P = 0.001) with those from the lowest incomes consistently consuming significantly less than those from the highest. DQI-A was positively correlated with iron intakes for 11-14 (P = 0.001) and 15-18 years (P < 0.001). Forty-one percent of 15-18-year-olds plasma ferritin stores were below the 15 µg L-1 and 21% had some form of anaemia. Cereal and cereal products were the greatest contributors to iron in all groups. CONCLUSION: Females in the lowest income groups are at greater risk of lower overall diet quality and inadequate iron and zinc intakes. Amongst older adolescents, there is evidence of iron stores being depleted and an increased prevalence of anaemia.

Vegans and vegetarians living in Nottingham (UK) continue to be at risk of iodine deficiency.

Iodine is essential for thyroid hormone synthesis. Individuals adhering to vegan and vegetarian diets have been found to be vulnerable to iodine deficiency. Yet, iodine has not been monitored in these groups across time. This study aims to investigate iodine status, intake and knowledge in vegans, vegetarians and omnivores and determine changes between 2016-2017 and 2019. Dietary intake (µg/d) was estimated by 3-d food diaries and iodine FFQ. Urinary iodine concentration, analysed by inductively coupled plasma mass spectrometry, assessed iodine status according to WHO criteria. Iodine knowledge was scored by an adapted questionnaire. IBM SPSS was used for statistical analysis. Ninety-six adults (18-60 years) were recruited in October 2016-2017 (vegans: 12; vegetarians: 5; omnivores: 43) and June 2019 (vegans: 7; vegetarians: 10;omnivores: 19). Median dietary iodine was below the Reference Nutrient Intake for all groups. Vegans and vegetarians had the lowest iodine intake. Vegans had significantly lower iodine intake than omnivores (2016-2017, P = 0 032; 2019, P = 0 001). Omnivores had the highest iodine status (2016-2017, 79 4 µg/l; 2019, 72 4 µg/l) and vegans the lowest (2016-2017, 31 2 µg/l; 2019, 12 2 µg/l). Iodine knowledge was poor but did not differ between dietary groups (2016-2017, P = 0 219; 2019, P = 0 532). Vegans and vegetarians continue to be at risk of iodine deficiency. Further, iodine intake in the UK is poor independent of dietary choice. Iodine education is needed along with research into improving iodine nutrition at national level.

Remote effects of acute kidney injury in a porcine model.

Acute kidney injury (AKI) is a common and serious condition with no specific treatment. An episode of AKI may affect organs distant from the kidney, further increasing the morbidity associated with AKI. The mechanism of organ cross talk after AKI is unclear. The renal and immune systems of pigs and humans are alike. Using a preclinical animal (porcine) model, we tested the hypothesis that early effects of AKI on distant organs is by immune cell infiltration, leading to inflammatory cytokine production, extravasation, and edema. In 29 pigs exposed to either sham surgery or renal ischemia-reperfusion (control, n = 12; AKI, n = 17), we assessed remote organ (liver, lung, brain) effects in the short (from 2- to 48-h reperfusion) and longer term (5 wk later) using immunofluorescence (for leukocyte infiltration, apoptosis), a cytokine array, tissue elemental analysis (e.g., electrolytes), blood hematology and chemistry (e.g., liver enzymes), and PCR (for inflammatory markers). AKI elicited significant, short-term (∼24 h) increments in enzymes indicative of acute liver damage (e.g. , AST: ALT ratio; P = 0.02) and influenced tissue biochemistry in some remote organs (e.g., lung tissue [Ca(2+)] increased; P = 0.04). These effects largely resolved after 48 h, and no further histopathology, edema, apoptosis, or immune cell infiltration was noted in the liver, lung, or hippocampus in the short and longer term. AKI has subtle biochemical effects on remote organs in the short term, including a transient increment in markers of acute liver damage. These effects resolved by 48 h, and no further remote organ histopathology, apoptosis, edema, or immune cell infiltration was noted.

Remote conditioning or erythropoietin before surgery primes kidneys to clear ischemia-reperfusion-damaged cells: a renoprotective mechanism?

Acute kidney injury is common, serious with no specific treatment. Ischemia-reperfusion is a common cause of acute kidney injury (AKI). Clinical trials suggest that preoperative erythropoietin (EPO) or remote ischemic preconditioning may have a renoprotective effect. Using a porcine model of warm ischemia-reperfusion-induced AKI (40-min bilateral cross-clamping of renal arteries, 48-h reperfusion), we examined the renoprotective efficacy of EPO (1,000 iu/kg iv.) or remote ischemic preconditioning (3 cycles, 5-min inflation/deflation to 200 mmHg of a hindlimb sphygmomanometer cuff). Ischemia-reperfusion induced significant kidney injury at 24 and 48 h (χ(2), 1 degree of freedom, >10 for 6/7 histopathological features). At 2 h, a panel of biomarkers including plasma creatinine, neutrophil gelatinase-associated lipocalin, and IL-1ß, and urinary albumin:creatinine could be used to predict histopathological injury. Ischemia-reperfusion increased cell proliferation and apoptosis in the renal cortex but, for pretreated groups, the apoptotic cells were predominantly intratubular rather than interstitial. At 48-h reperfusion, plasma IL-1ß and the number of subcapsular cells in G2-M arrest were reduced after preoperative EPO, but not after remote ischemic preconditioning. These data suggest an intrarenal mechanism acting within cortical cells that may underpin a renoprotective function for preoperative EPO and, to a limited extent, remote ischemic preconditioning. Despite equivocal longer-term outcomes in clinical studies investigating EPO as a renoprotective agent in AKI, optimal clinical dosing and administration have not been established. Our data suggest further clinical studies on the potential renoprotective effect of EPO and remote ischemic preconditioning are justified.

Detecting iodine deficiency risks from dietary transitions using shopping data.

Plant-based product replacements are gaining popularity. However, the long-term health implications remain poorly understood, and available methods, though accurate, are expensive and burdensome, impeding the study of sufficiently large cohorts. To identify dietary transitions over time, we examine anonymised loyalty-card shopping records from Co-op Food, UK. We focus on 10,626 frequent customers who directly replaced milk with alternative milk. We then use product nutritional information to estimate weekly nutrient intake before and after the transition. 83% who converted to alternative milk saw a fall in iodine (44%), calcium (30%) and vitamin B12 (39%) consumption, with 57% reducing iodine purchase by more than 50%. The decline is even higher for those switching dairy and meat products. Our findings suggest that dietary transitions - such as replacing milk with alternative milk - could lead to nutritional deficiencies, notably iodine, which, if not addressed, may represent a significant public health concern, particularly in countries which do not mandate salt iodisation.

The Impact of Drugs on Hydrogen Sulfide Homeostasis in Mammals.

Mammalian cells and tissues have the capacity to generate hydrogen sulfide gas (H2S) via catabolic routes involving cysteine metabolism. H2S acts on cell signaling cascades that are necessary in many biochemical and physiological roles important in the heart, brain, liver, kidney, urogenital tract, and cardiovascular and immune systems of mammals. Diminished levels of this molecule are observed in several pathophysiological conditions including heart disease, diabetes, obesity, and immune function. Interestingly, in the last two decades, it has become apparent that some commonly prescribed pharmacological drugs can impact the expression and activities of enzymes responsible for hydrogen sulfide production in cells and tissues. Therefore, the current review provides an overview of the studies that catalogue key drugs and their impact on hydrogen sulfide production in mammals.

Adoption of a Short-Term (4-Week) Vegan Diet as Part of 'Veganuary' Significantly Reduces Saturated Fatty Acid (SFA), Cholesterol, B12, and Iodine Intake in Omnivorous Individuals-An Observational Study.

Global veganism campaigns like 'Veganuary' have gained popularity. We conducted an observational study to assess the impact of a 4-week vegan diet during 'Veganuary' on nutrient intake, status, knowledge, and motivations for veganism. Data were collected before and after 'Veganuary', using Food Frequency Questionnaires (FFQs) to estimate dietary intake. Micronutrient knowledge and motivation were assessed through questionnaires. A total of 154 UK adults aged 18-60 years (2019: n81; 2020: n73) participated. Groups were vegetarians and omnivores committed to a 4-week vegan diet during 'Veganuary'. Control groups were vegans and omnivores who did not transition. Short-term vegan diets significantly decreased intake of iodine, B12, cholesterol, and saturated fatty acids (SFAs) in omnivores. Micronutrient knowledge was low, and motivation for veganism varied. Short-term vegan diets reduce macro- and micronutrient intake in omnivores. Veganuary participants could benefit from nutritional guidance or supplementation. Attention is required for UK micronutrient intake and knowledge. Motivations for vegan pledges may influence diets, warranting further research.

The Impact of the COVID-19 Pandemic on the Food Security of UK Adults Aged 20-65 Years (COVID-19 Food Security and Dietary Assessment Study).

The first UK lockdown greatly impacted the food security status of UK adults. This study set out to establish if food procurement was adapted differently for different income groups and if this impacted dietary intakes disproportionately. Adults (n = 515) aged 20-65 years participated in an online survey with 56 completing a 3-4 day diet diary. Food availability was a significant factor in the experience of food insecurity. Similar proportions of food secure and food insecure adapted food spend during lockdown, spending similar amounts. Food insecure (n = 85, 18.3%) had a 10.5% lower income and the money spent on food required a greater proportion of income. Access to food was the biggest driver of food insecurity but monetary constraint was a factor for the lowest income group. The relative risk of food insecurity increased by 0.07-fold for every 1% increase in the proportion of income spent on food above 10%. Micronutrient intakes were low compared to the reference nutrient intake (RNI) for most females, with riboflavin being 36% lower in food insecure groups (p = 0.03), whilst vitamin B12 was 56% lower (p = 0.057) and iodine 53.6% lower (p = 0.257) these were not significant. Coping strategies adopted by food insecure groups included altering the quantity and variety of fruit and vegetables which may have contributed to the differences in micronutrients.

Protein restriction in the pregnant mouse modifies fetal growth and pulmonary development: role of fetal exposure to {beta}-hydroxybutyrate.

Maternal undernutrition during sensitive periods of pregnancy results in offspring predisposed towards the development of a number of diseases of adulthood, including hypertension and diabetes. In order to determine the nature of any gross alterations in fetal growth during early organogenesis, we supplied timed-mated pregnant mice with diets containing 6% protein (6%P), 9% protein (9%P) or 18% protein (18%P; control) from day 0 of pregnancy. At embryonic days 11 (E11), 12 (E12) and 13 (E13), females were killed and fetuses removed. Gross morphological analysis revealed that fetal limb growth was impaired between E11 and E12 in 6%P animals, but this recovered by E13. Likewise, fetal liver growth and lung branching morphogenesis were seen to exhibit an initial growth impairment at E12 followed by a rapid recovery by E13. Coincident with the observed changes in fetal growth, we noted an elevation in maternal hepatic triglyceride content, expression of the ketogenic 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) and circulating plasma ß-hydroxybutyrate (BOHB). In addition, fetal liver Hmgcs2 expression was switched on by E13 in both 6%P- and 9%P-exposed animals. Exogenous BOHB did not influence branching morphogenesis in fetal lung explant cultures; however, we cannot rule out the possibility that this may occur in vivo. In conclusion, we find that disturbance of fetal growth by maternal dietary protein restriction is associated and therefore potentially indicated by changes in maternal and fetal ketone body metabolism.

Corticosteroid-induced kidney dysmorphogenesis is associated with deregulated expression of known cystogenic molecules, as well as Indian hedgehog.

An intact genome is essential for kidney growth and differentiation, but less is known about whether, and how, an altered fetal milieu modifies these processes. Maternal low-protein diets perturb growth of the metanephros, the precursor of the mature kidney. Fetal corticosteroid overexposure may, in part, mediate this, because such diets downregulate placental 11beta-hydroxysteroid dehydrogenase-2, which degrades maternal corticosteroids. We report that glucocorticoid and mineralocorticoid receptors are expressed in mouse metanephric epithelia. Metanephroi maintained in organ culture with hydrocortisone (1.4 or 14 microM) underwent a dose-dependant deceleration of overall growth accompanied by cyst formation. Dexamethasone, a glucocorticoid, reproduced these outcomes, but aldosterone, a mineralocorticoid, did not. Hydrocortisone upregulated transcripts levels of cadherin-11 and downregulated prospero-related homeobox-1, hence mimicking reported effects of maternal low-protein diet. Hydrocortisone also upregulated transcripts encoding Na(+)-K(+)-ATPase subunits and ligands for the epidermal growth factor receptor, all previously implicated in renal cyst growth. The most upregulated transcript, however, was indian hedgehog, and the encoded protein was immunodetected in metanephric cysts. Furthermore, in the presence of hydrocortisone, cystogenesis, but not whole organ growth, was significantly reduced by cyclopamine, a drug downregulating hedgehog signaling. Finally, both glucocorticoid receptor and indian hedgehog proteins were detected by immunohistochemistry in cystic tubules within human dysplastic kidneys, consistent with the hypothesis that these molecules modify the severity of this congenital malformation. Collectively, our observations raise the possibility that enhanced hedgehog signaling is an important stimulus for renal cyst formation. Furthermore, pharmacological inhibition of this pathway should be explored as a potential therapy for renal cystic diseases, starting with relevant animal models.

Trace Mineral Intake and Deficiencies in Older Adults Living in the Community and Institutions: A Systematic Review.

The global population is ageing with many older adults suffering from age-related malnutrition, including micronutrient deficiencies. Adequate nutrient intake is vital to enable older adults to continue living independently and delay their institutionalisation, as well as to prevent deterioration of health status in those living in institutions. This systematic review investigated the insufficiency of trace minerals in older adults living independently and in institutions. We examined 28 studies following a cross-sectional or cohort design, including 7203 older adults (≥60) living independently in 13 Western countries and 2036 living in institutions in seven Western countries. The estimated average requirement (EAR) cut-off point method was used to calculate percentage insufficiency for eight trace minerals using extracted mean and standard deviation values. Zinc deficiency was observed in 31% of community-based women and 49% of men. This was higher for those in institutional care (50% and 66%, respectively). Selenium intakes were similarly compromised with deficiency in 49% women and 37% men in the community and 44% women and 27% men in institutions. We additionally found significant proportions of both populations showing insufficiency for iron, iodine and copper. This paper identifies consistent nutritional insufficiency for selenium, zinc, iodine and copper in older adults.

Vegans, Vegetarians, and Omnivores: How Does Dietary Choice Influence Iodine Intake? A Systematic Review.

Vegan and vegetarian diets are becoming increasingly popular. Dietary restrictions may increase the risk of iodine deficiency. This systematic review aims to assess iodine intake and status in adults following a vegan or vegetarian diet in industrialised countries. A systematic review and quality assessment were conducted in the period May 2019-April 2020 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were identified in Ovid MEDLINE, Embase, Web of Science, PubMed, Scopus, and secondary sources. Fifteen articles met inclusion criteria. Participants included 127,094 adults (aged ≥ 18 years). Vegan groups presented the lowest median urinary iodine concentrations, followed by vegetarians, and did not achieve optimal status. The highest iodine intakes were recorded in female vegans (1448.0 ± 3879.0 µg day-1) and the lowest in vegetarians (15.6 ± 21.0 µg day-1). Omnivores recorded the greatest intake in 83% of studies. Seaweed contributed largely to diets of vegans with excessive iodine intake. Vegans appear to have increased risk of low iodine status, deficiency and inadequate intake compared with adults following less restrictive diets. Adults following vegan and vegetarian diets living in countries with a high prevalence of deficiency may be more vulnerable. Therefore, further monitoring of iodine status in industrialised countries and research into improving the iodine intake and status of adults following vegan and vegetarian diets is required.

Geographical and seasonal variation in iodine content of cow's milk in the UK and consequences for the consumer´s supply.

BACKGROUND: Dairy products provide a crucial source of dietary iodine for the majority of the UK population, contributing approximately 30-40 % of daily intake. Fluctuations in the iodine content of purchased milk both seasonally and annually implies potential fragility of iodine supply likely through fluctuating supplementation practices in cow herds. We set out to establish the level of national variation in herds and identify factors which might impact milk iodine content. METHODS: Milk samples were obtained from 98 herds across the UK via the National Milk Laboratories in August and December 2016. Iodine concentration of samples was measured using ICP-MS. Milk samples and feed intake data were additionally taken from 22 cows from the University of Nottingham (UON) dairy herd. RESULTS: There was considerable variation in milk iodine content from < 0.012 (Limit of Detection) to 1558 µg L-1, with a summer median of 197 µg L-1 and winter median 297 µg L-1. Overall, winter values were higher than summer counterparts (P < 0.001) and this held true for samples taken from the North West (P = 0.002) and South West (P = 0.006) but not for other regions studied. Data from the UON herd showed a negative relationship between iodine content and milk yield (P = 0.03) and we found that milk iodine content varied considerably despite apparently similar iodine intakes. CONCLUSIONS: Regional differences in milk iodine concentration between summer and winter suggests that feeding practices are far from uniform across the country. The negative association observed between iodine concentration and milk yield in UON samples, suggests that reduced summer values may be influenced by dilution in addition to seasonal differences in concentrate feed provision.

A novel liver specific isoform of the rat LAR transcript is expressed as a truncated isoform encoded from a 5'UTR located within intron 11.

BACKGROUND: The leukocyte common antigen related receptor (LAR) protein has been shown to modulate the signal transduction of a number of different growth factors, including insulin and insulin-like growth factor 1. Splice variants exhibit differing roles and are expressed according to tissue type and developmental stage. RESULTS: Using 5'RACE, we identified a 5'UTR within intron 11 of the rat LAR gene. We demonstrated that this gives rise to a novel isoform of the LAR transcript encoded from the identified region within intron 11. By priming across the site from exon 11 to exon 15 we show that the novel 5'UTR is not represented in the full-length transcript and thus, it produces a truncated form of the LAR mRNA. We examined the tissue distribution of this novel isoform and found it to be exclusively expressed in liver. We additionally identified a liver specific 150 kDa band with western blotting which we propose may represent the protein product of the novel transcript. Luciferase assays showed the region immediately upstream of the 5'UTR to possesses considerable promoter activity and that this may be conferred by the presence of a number of putative binding sites for liver enriched transcription factors. CONCLUSION: In summary, we describe a novel, liver specific, truncated isoform of the LAR transcript transcribed under the control of an intronic promoter, potentially representing a previously unidentified modulator of hepatic insulin signalling.

Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension.

Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Lifelong environmental factors (eg, salt intake, obesity, alcohol) and genetic factors clearly contribute to the development of hypertension, but it has also been established that stress in utero may program the later development of the disease. This phenomenon, known as fetal programming can be modeled in a range of experimental animal models. In maternal low protein diet rat models of programming, administration of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists in early life can prevent development of hypertension, thus implicating the renin-angiotensin system in this process. Here we show that in this model, expression of the AT(1b) angiotensin receptor gene in the adrenal gland is upregulated by the first week of life resulting in increased receptor protein expression consistent with the increased adrenal angiotensin responsiveness observed by others. Furthermore, we show that the proximal promoter of the AT(1b) gene in the adrenal is significantly undermethylated, and that in vitro, AT(1b) gene expression is highly dependent on promoter methylation. These data suggest a link between fetal insults to epigenetic modification of genes and the resultant alteration of gene expression in adult life leading ultimately to the development of hypertension. It seems highly probable that similar influences may be involved in the development of human hypertension.