Later Development Of Hypertension Research Articles

Relationship between psychological distress, health behaviours and future reports of hypertension among adults in East Zimbabwe: a cohort study

IntroductionExtensive cross-sectional evidence has demonstrated an association between psychological distress (PD) and hypertension. However, evidence on the temporal relationship is limited, especially in low-income and middle-income countries. The role of...

Migrating Populations and Health: Risk Factors for Cardiovascular Disease and Metabolic Syndrome.

Purpose of ReviewTo summarize results of recent studies of migrants in Europe and North America and ongoing efforts to adapt strategies to provide them with inclusive sensitive health care.Recent FindingsMajor predisposing factors for developing hypertension, obesity, diabetes, and the metabolic syndrome in migrating populations and refugees were identified. Susceptibility to the metabolic syndrome is predominantly due to environmental factors and psychological stress. Acculturation also contributes to the emergence of cardiovascular (CV) risk factors in first-generation adult immigrants. Increased risk for later development of hypertension and dyslipidemia has also been detected in adolescent immigrants. Targets for public health efforts were based on data that show important differences in CV risk factors and prevalence of the metabolic syndrome among ethnic immigrant groups. Studies in young adults focused on lifestyle and dietary behaviors and perceptions about weight and body image, while the focus for older adults was end-of-life issues.SummaryTwo important themes have emerged: barriers to health care, with a focus on cultural and language barriers, and violence and its impact on immigrants’ mental health.

ASSOCIATION BETWEEN PSYCHOLOGICAL DISTRESS AND LATER REPORTS OF HYPERTENSION AMONG ADULTS IN EAST ZIMBABWE

Objective: Little is known about the temporal relationship between psychological distress (PD) and hypertension, especially in low-income countries. We assessed the association between PD and later development of hypertension among Zimbabwean adults, and the role of smoking, alcohol consumption and recreational drug use in this relationship. Design and method: Data were taken from the Manicaland Study, an open cohort study in east Zimbabwe. Participants aged 15–54 were surveyed in 2012/2013 and followed-up in 2018/19. At baseline, PD was assessed using the Shona Symptom Questionnaire, a screening tool developed and validated in Shona-speaking countries. Participants self-reported whether they were currently: smokers; took drugs for pleasure; or regularly visited bars and/or consumed over three alcoholic drinks per sitting. At baseline and follow-up, participants reported whether they had ever been diagnosed with hypertension by a doctor/nurse. We selected individuals who did not report hypertension at baseline and used logistic regression to examine associations between baseline PD and hypertension at follow-up, controlling for sociodemographic and economic confounders. We also explored the effect of including binary variables capturing smoking status, drug use and alcohol consumption in the model. Results: 742 participants who completed baseline and follow-up surveys, were not hypertensive at baseline, and had full covariate data, were included. At baseline, 10.4% of these had PD, and at follow-up 17.5% (overall) had developed hypertension. The odds of developing hypertension were 2.01 (95% Confidence Interval = 1.14–3.54) times higher among those with PD at baseline, after adjustment for sociodemographic and economic confounders (Table 1). Introducing smoking status, drug use and alcohol consumption into the model had little effect on our findings (adjusted Odds Ratio, aOR:2.04, 1.16–3.59) and we had little evidence that these behaviours were independently associated with hypertension (aORs:smoking:1.41, 0.40–4.98; alcohol consumption:1.49, 0.61–3.66; drug use:0.49, 0.14–1.75). Conclusions: PD was associated with increased odds of developing hypertension in Manicaland. However, we did not find strong evidence that smoking status, drug use and alcohol consumption contributed to this relationship, which may reflect the low prevalence of these behaviours in our study. The results suggest mental health interventions may be beneficial for reducing hypertension in Zimbabwe.

Maternal risk of hypertension 7-15 years after pregnancy: clues from the placenta.

To assess whether pre-eclampsia (PE)-related placental/extraplacental membrane findings are linked to moderately elevated blood pressure (BP) in pregnancy and later-life hypertension. Prospective cohort. 52 prenatal clinics, 5 Michigan communities. The POUCH Study recruited women at 16-27weeks' gestation (1998-2004) and studied a sub-cohort in depth. This sample (n=490) includes sub-cohort women with detailed placental assessments and cardiovascular health evaluations 7-15years later in the POUCHmoms follow-up study. PE-related placental/extraplacental membrane findings (i.e. mural hyperplasia, unaltered/abnormal vessels or atherosis in decidua; infarcts) were evaluated in relation to pregnancy BP and odds of Stage 2 hypertension at follow up using weighted polytomous regression. Follow-up hypertension odds also were compared in three pregnancy BP groups: normotensives (referent) and moderately elevated BP with or without PE-related placental/extraplacental membrane findings. Stage 2 hypertension (SBP≥140mmHg and/or DBP≥90mmHg, or using antihypertensive medications) at follow up. After excluding women with pregnancy hypertension (i.e. chronic, PE, gestational), mural hyperplasia and unaltered/abnormal decidual vessels were each associated with Stage 2 hypertension at follow up: adjusted odds ratio (aOR)=2.7, 95% CI 1.1-6.6, and aOR = 1.7 (95% CI 0.8-3.4), respectively. Women with moderately elevated BP in pregnancy and evidence of mural hyperplasia or unaltered/abnormal decidual vessels had greater odds of Stage 2 hypertension at follow up: aOR=4.5 (95% CI 1.6-12.5 and aOR=2.6, 95% CI 1.1-5.9, respectively. PE-related placental/extraplacental membrane findings help risk-stratify women with moderately elevated BP in pregnancy for later development of hypertension. Placental findings associated with mother's risk of later-life hypertension.

SUN-132 PRETERM BIRTH: LONG-TERM EFFECTS ON RENAL MORPHOLOGY AND GLOMERULAR CAPILLARISATION IN ADULT SHEEP

Preterm birth (delivery < 37 weeks of gestation) is an important risk factor for the later development of hypertension and chronic kidney disease. The exact cause of this association is unknown, but likely relates to impaired kidney development in early life. We have previously shown that preterm birth can result in the formation of glomeruli with shrunken capillary tufts in the kidneys of human preterm neonates. We have also shown, in lambs, that preterm birth and/or postnatal mechanical ventilation lead to substantial reductions in glomerular capillary length and filtration surface area at 3 days after birth. If this persists, it has the potential to cause glomerulosclerosis and renal dysfunction. Therefore, in this study we aimed to determine the long-term impact of preterm birth on glomerular morphology in adult sheep. Singleton male sheep were delivered moderately preterm at 132 days (~0.9) of gestation or at term (146 days of gestation). The ewes assigned to deliver preterm were administered 11.4mg betamethasone at 48 and 24 hours prior to birth, and the preterm sheep did not require mechanical ventilation postnatally. After weaning, the Preterm (n=6) and Term (n=6) sheep were maintained in natural grass paddocks and were euthanised at 14.5 months of age (early adulthood). The right kidney from each sheep was perfusion-fixed, and stereological methods were used to determine mean renal corpuscle and glomerular volumes, and glomerular capillary length and surface area in the outer, mid, and inner regions of the renal cortex. Glomerulosclerosis, and interstitial collagen levels in the medulla and cortex, were assessed histologically. Sheep born preterm were on average 2.5 kg lighter at birth than those born at term (p=0.0001), but at 14.5 months of age there was no difference between the Term and Preterm sheep in body or kidney weight (Term: 128 ± 8 g, Preterm: 121 ± 5 g, p=0.45). Renal corpuscle volume was significantly (p=0.03) larger in the Preterm sheep than the Term sheep (e.g. mean for inner cortex – Term: 0.0018 ± 0.0001 mm3, Preterm: 0.0024 ± 0.0003 mm3) with the Preterm sheep exhibiting enlarged Bowman’s spaces; however, there was no difference in glomerular volume between groups. Similarly, preterm birth did not impact mean glomerular capillary length or surface area per glomerulus in adult sheep. There was also no difference between groups in interstitial collagen levels, or glomerulosclerosis index. Although there is some evidence of morphological changes in the kidneys following preterm birth, findings suggest that moderate preterm birth per se does not adversely affect total renal filtration surface area or result in renal disease in early adulthood. It is now important to determine whether glomerular capillarisation is similarly normalised in preterm-born adults that were exposed to mechanical ventilation in the neonatal period.

Hydronephrosis and risk of later development of hypertension.

Congenital ureteral obstruction is a fairly common condition in infants, and its clinical management has been long debated during the last decade. The long-term physiological consequences of today's conservative non-surgical management in many asymptomatic hydronephrotic children are unclear. Experimental studies in rats and mice, retrospective studies in children and adults, as well as prospective studies in children are included in this mini review. Experimental models of hydronephrosis in rats and mice have demonstrated that partial ureteropelvic junction obstruction (UPJO) is casually linked with development of hypertension and renal injuries in later life. The mechanisms are multifactorial and involve increased activity of the renin-angiotensin-aldosterone system and renal sympathetic nerve activity. Furthermore, oxidative stress and nitric oxide deficiency in the affected kidney appear to play important roles in the development and maintenance of hypertension. Clinical case reports in adults and recent prospective studies in children have associated hydronephrosis with elevated blood pressure, which could be reduced by surgical management of the obstruction. Based on current experimental and clinical knowledge regarding the link between partial UPJO and changes in blood pressure, it is proposed that today's non-operative management of hydronephrosis should be reconsidered to reduce the risk of developing elevated blood pressure or hypertension in later life.

Commentary to ‘Multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (UTD classification system)’

[65] Ulman I, Jayanthi VR, Koff SA. The long-term followup of newborns with severe unilateral hydronephrosis initially treated nonoperatively. J Urol 2000;164:1101e5. [66] Braga LH, Mijovic H, Farrokhyar F, Pemberton J, DeMaria J, Lorenzo AJ. Antibiotic prophylaxis for urinary tract infections in antenatal hydronephrosis. Pediatrics 2013;131:e251e61. [67] Gimpel C, Masioniene L, Djakovic N, Schenk JP, Haberkorn U, Tonshoff B, et al. Complications and long-term outcome of primary obstructive megaureter in childhood. Pediatr Nephrol 2010;25:1679e86. [68] Davenport MT, Merguerian PA, Koyle M. Antenatally diagnosed hydronephrosis: current postnatal management. Pediatr Surg Int 2013;29:207e14. [69] Kose E, Yavascan O, Turan O, Kangin M, Bal A, Alparslan C, et al. The effect of circumcision on the frequency of urinary tract infection, growth and nutrition status in infants with antenatal hydronephrosis. Ren Fail 2013;35:1365e9. [70] Wong CJ, Moxey-Mims M, Jerry-Fluker J, Warady BA, Furth SL. CKiD (CKD in children) prospective cohort study: a review of current findings. Am J Kidney Dis 2012;60:1002e11. [71] Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec 1992;232:194e201. [72] Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 1981; 241:F85e93. [73] Remuzzi G, Ruggenenti P, Perico N. Chronic renal diseases: renoprotective benefits of renin-angiotensin system inhibition. Ann Int Med 2002;136:604e15. [74] Ardissino G, Dacco V, Testa S, Bonaudo R, Claris-Appiani A, Taioli E, et al. Epidemiology of chronic renal failure in children: data from the ItalKid project. Pediatrics 2003;111: e382e7. [75] Quirino IG, Diniz JS, Bouzada MC, Pereira AK, Lopes TJ, Paixao GM, et al. Clinical course of 822 children with prenatally detected nephrouropathies. Clin J Am Soc Nephrol 2012;7:444e51. [76] Carlstrom M. Causal link between neonatal hydronephrosis and later development of hypertension. Clin Exp Pharmacol Physiol 2010;37:e14e23. [77] Jodal U. The natural history of bacteriuria in childhood. Infect Dis Clin North Am 1987;1:713e29. [78] Kogon AJ, Pierce CB, Cox C, Brady TM, Mitsnefes MM, Warady BA, et al. Nephrotic-range proteinuria is strongly associated with poor blood pressure control in pediatric chronic kidney disease. Kidney Int 2014;85:938e44. [79] Navis G, Faber HJ, de Zeeuw D, de Jong PE. ACE inhibitors and the kidney. A risk-benefit assessment. Drug Saf 1996;15: 200e11. [80] Ruster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol 2006;17: 2985e91. [81] Martens DH, Rake JP, Navis G, Fidler V, van Dael CM, Smit GP. Renal function in glycogen storage disease type I, natural course, and renopreservative effects of ACE inhibition. Clin J Am Soc Nephrol 2009;4:1741e6. [82] Reddy UM, Abuhamad AZ, Levine D, Saade GR, Fetal Imaging Workshop Invited P. Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging Workshop. J Ultrasound Med 2014;33:745e57.

Impaired EphA4 signaling leads to congenital hydronephrosis, renal injury, and hypertension

Experimental hydronephrosis induced by partial ureteral obstruction at 3 wk of age causes hypertension and renal impairment in adult rats and mice. Signaling by Ephrin receptors (Eph) and their ligands (ephrins) importantly regulates embryonic development. Genetically modified mice, where the cytoplasmic domain of the EphA4 receptor has been substituted by enhanced green fluorescent protein (EphA4gf/gf), develop spontaneous hydronephrosis and provide a model for further studies of the disorder. The present study aimed to determine if animals with congenital hydronephrosis develop hypertension and renal injuries, similar to that of experimental hydronephrosis. Ultrasound and Doppler techniques were used to visualize renal impairment in the adult mice. Telemetric blood pressure measurements were performed in EphA4gf/gf mice and littermate controls (EphA4+/+) during normal (0.7% NaCl)- and high (4% NaCl)-sodium conditions. Renal excretion, renal plasma flow, and glomerular filtration were studied, and histology and morphology of the kidneys and ureters were performed. EphA4gf/gf mice developed variable degrees of hydronephrosis that correlated with their blood pressure level. In contrast to EphA4+/+, the EphA4gf/gf mice displayed salt-sensitive hypertension, reduced urine concentrating ability, reduced renal plasma flow, and lower glomerular filtration rate. Kidneys from EphA4gf/gf mice showed increased renal injuries, as evidenced by fibrosis, inflammation, and glomerular and tubular changes. In conclusion, congenital hydronephrosis causes hypertension and renal damage, similar to that observed in experimentally induced hydronephrosis. This study further reinforces the supposed causal link between hydronephrosis and later development of hypertension in humans.

Pregnancy Complications and Later Development of Hypertension

Pregnancy complications such as preeclampsia and diabetes affect approximately 5 to 10 % of all pregnancies and compromise maternal and fetal health during gestation. Complications during pregnancy may also contribute to the development of hypertension and future cardiovascular risk in the mother. Moreover, fetal exposure to hypertension and diabetes during pregnancy can program hypertension and cardiovascular disease in the offspring. Transgenerational transmission of programmed cardiovascular risk highlights the importance of understanding the mechanisms that link complications during pregnancy with later hypertension in her offspring and subsequent generations. However, experimental studies are needed to investigate the cause and effect of increased blood pressure in the mother following a complicated pregnancy and provide insight into the development of preventative measures that may improve the long-term cardiovascular health of women and their offspring.

Hypertensive Disorders of Pregnancy - A Life-Long Risk?!

Background: Arterial hypertension is one of the most important causes of cardiovascular diseases, and the latter are responsible for almost half of the deaths in the industrialised nations. Hypertensive disorders of pregnancy constitute one of the most frequent causes of feto-maternal morbidity and mortality; on the other hand the occurrence of a hypertensive disorder of pregnancy represents a risk for the later development of hypertension and the cardiovascular risks resulting therefrom. The aim of this article is to demonstrate the association of hypertensive disorders of pregnancy with consecutive cardiovascular diseases. Materials and Methods: Specific selective literature research. Results: After the occurrence of a hypertensive disorder of pregnancy the relative risks for hypertension are 3.7 (2.70-5.05), for ischaemic heart disease 2.2 (1.86-2.52), for cerebral insult 1.8 (1.45-2.27) and for mortality resulting from cardiovascular causes 1.5 (1.05-2.14) and are thus significant. According to a recent study 56 % of internal specialists and 23 % of gynecologists do not know about the association of preeclampsia with ischemic heart disease, 48 % and 38 % respectively are not aware of the link with stroke and 79 % and 77 % respectively are not aware of the association with a reduced life expectancy after preeclampsia. The presence of hypertension is not known by many of the patients, merely 28-38 % receive an appropriate therapy. Conclusion: Adequate follow-up after hypertensive disorders of pregnancy and the early recognition of and therapy for hypertension represent the cornerstones in the prevention of late cardiovascular sequelae. General practitioners, specialist for internal medicine and gynaecologists have a special responsibility with regard to the reduction of later complications.

Use of ultrasound to assess renal reperfusion and P-selectin expression following unilateral renal ischemia

Renal ischemia-reperfusion injury is a major cause of acute kidney injury that carries a high mortality rate and increases the risk of later development of hypertension and chronic kidney disease. Although mouse models have contributed much to our understanding of the mechanisms involved, studying aspects of the injury process in vivo remains technically challenging. This study validates the use of noninvasive ultrasound imaging to assess both renal perfusion and vascular adhesion molecule expression following 1-h unilateral renal ischemia in male and female mice. Pulsed-wave Doppler measurements of renal arterial blood velocity revealed renal perfusion recoveries of 56 ± 9% in male and 69 ± 10% in female mice 1 h after the commencing of reperfusion, which is similar to what we have previously published using conventional invasive methodology. At 24 h postischemia, renal perfusion was 40 ± 8% in male and 46 ± 7% in female mice, representing a further significant reduction of perfusion (P(Time) < 0.001). Using ultrasound imaging of a P-selectin-targeted contrast agent, a significant increase in vascular P-selectin protein expression was observed after 1-h reperfusion in the cortex of the postischemic compared with contralateral kidney in both male and female mice (18 ± 5 vs. 3 ± 3 intensity units in male and 30 ± 6 vs. 0 ± 4 in female mice, P(Ischemia) < 0.01). An approximately sixfold increase in P-selectin mRNA was observed ex vivo in the renal vasculature of male and female mice at this time point (P < 0.01). In conclusion, ultrasound represents an effective and noninvasive method for the measurement of both renal perfusion and vascular adhesion molecule expression in mice.

Above Which Blood Pressure Level Does the Risk of Atrial Fibrillation Increase?

See related article, pp 198–204 Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, occurs in 1% to 2% of the general population,1 and its incidence is growing. Mostly because of the progressive aging of the population, the prevalence of AF is expected to double over the next 50 years.1 AF is a potentially devastating condition for several reasons. It portends a 5-fold risk of stroke,2 and ischemic strokes that occur in people with AF are often fatal or leave surviving patients generally more disabled and at higher risk of recurrences compared with other causes of stroke. AF triples the risk of heart failure,3 doubles the risk of dementia, and markedly increases the risk of all-cause mortality.4 For the above reasons, prevention of AF through appropriate control of its modifiable risk factors is a public health priority. Unfortunately, despite numerous experimental and clinical studies, the individual risk of developing AF in a given time frame is still difficult to estimate.5 Hypertension is a well-known modifiable risk factor for AF,3,4 although it is unclear above which blood pressure (BP) level the risk of AF definitely increases and, even more important, which target BP level should be pursued to reduce the risk of AF in treated hypertensive patients. In a population based, case-control study of 433 patients with incident AF and 899 controls, the risk of AF doubled in participants with systolic BP ≥150 …

Arterial Stiffness in Prehypertension: A Possible Vicious Cycle

The pathophysiological abnormalities associated with increased arterial stiffness and/or abnormal pressure wave reflection may play crucial roles in increasing the risk of development of cardiovascular events. On the other hand, prehypertension, defined as a systolic blood pressure of 120-139 and/or a diastolic blood pressure of 80-89 mmHg, is a "danger zone" for the later development of hypertension and is also associated with an increased incidence of cardiovascular diseases and cardiovascular mortality. We discuss the association among arterial stiffness/pressure wave reflection, prehypertension, and the later development of hypertension. Several prospective studies have demonstrated that increased arterial stiffness/abnormal pressure wave reflection are risk factors for the later development of hypertension in subjects with prehypertension. On the contrary, persistence of prehypertention accelerates the age-related increase of the arterial stiffness. Thus, arterial stiffness and prehypertension may be elements of a vicious cycle, and other cardiovascular risk factors, such as aging and abnormal glucose metabolism, may aggravate this cycle. In the future, development of a simple technique to assess large/small arterial stiffness and an effective strategy to reduce arterial stiffness in subjects with prehypertension is warranted.

Causal link between neonatal hydronephrosis and later development of hypertension

1. Although congenital ureteral obstruction is a common disorder in infants, its pathophysiology remains poorly understood and its clinical management continues to be debated. During the past decade, the surgical management of non-symptomatic hydronephrosis in children has become more conservative, but the long-term physiological consequences of this new policy are unclear. 2. In experimental models with complete ureteral obstruction, tubular atrophy and interstitial inflammation occur rapidly. Although this type of obstruction is very rare in clinical practice, it is often referred to in clinical discussions. New studies, using a model with chronic partial ureteral obstruction, have demonstrated that hydronephrosis is associated with renal injuries and is causally related to hypertension. 3. The mechanisms underlying the development of hypertension in experimental hydronephrosis are complex and involve changes in both the renin-angiotensin system and renal sympathetic nerve activity. Furthermore, oxidative stress and nitric oxide deficiency in the diseased kidney, with consequent resetting of the tubuloglomerular feedback mechanism, appear to play a pivotal role in the development and maintenance of hyper-tension. 4. In view of the new knowledge regarding the long-term effects of partial ureteral obstruction, today's non-operative management of hydronephrosis should be reconsidered to prevent obstructive nephropathy and hypertension in later life.

Role of postnatal dietary sodium in prenatally programmed hypertension

In this study we examined the short- and long-term impact of early life dietary sodium (Na) on prenatally programmed hypertension. Hypertension was induced in rat offspring by a maternal low protein (LP) diet. Control and LP offspring were randomized to a high (HS), standard (SS), or low (LS) Na diet after weaning. On the SS diet, the LP pups developed hypertension by 6 weeks of age. The development of hypertension was prevented by the LS diet and exacerbated by the HS diet. Kidney nitrotyrosine content, a measure of oxidative stress, was reduced by the LS diet compared with the HS diet. The modified diets had no effect on control pups. A group of animals on the SS diet was followed up to 51 weeks of age after an early life 3-week exposure to the HS or LS diet. This brief early exposure of LP animals to the LS diet prevented the later development of hypertension and ameliorated the nephrosclerosis observed after early exposure to the HS diet. The LP offspring with early exposure to LS diet had lost their salt-sensitivity when challenged with the HS diet at the age of 43-49 weeks. No effect of early life dietary Na was observed in control animals. These results show that hypertension in this model is salt sensitive and may, in part, be mediated by salt-induced renal oxidative stress and that there may exist a developmental window which allows postnatal "reprogramming" of the hypertension.

Prevention and regression of hypertension: role of renal microvascular protection

Hypertension is a disease which affects over 26.4% of the world adult population, therefore novel approaches to the prevention and treatment of this disease need to be examined. Previous studies from our and other laboratories have shown that treatment of spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats with a renin-angiotensin system (RAS) inhibitor during the 'critical period' in hypertension development results in prevention of the later development of hypertension. In humans, Julius et al. reported similar findings in the landmark TROPHY study. Recently, we reported that 'pulse' treatment of SHR with high-dose angiotensin receptor blocker (ARB) is effective in causing sustained reduction of already established hypertension, even when the treatment was started after the 'critical period'. These results suggest the possibility that 'regression' of established hypertension may become feasible, and we have started a prospective, multicenter clinical study (STAR CAST study) to examine this possibility. In our animal studies, we found that treatment of rats during the 'critical period' with an ARB inhibits the development of renal arteriolar hypertrophy. Moreover, a high-dose angiotensin blocker caused a remarkable reversal of renal arteriolar hypertrophy in SHR, which was associated with changes in microvascular MMP expression. These results suggest that changes in the renal microvasculature may have an important role in the mechanisms of hypertension prevention and regression by ARB.

Deficiency of intrarenal angiotensin II type 2 receptor impairs paired homeo box-2 and N-myc expression during nephrogenesis

We previously demonstrated that angiotensin II (Ang II) stimulates paired homeo box-2 (Pax-2) via the Ang II type 2 receptor (AT(2)R). The Pax-2 gene and N-myc play pivotal roles in renal morphogenesis via their effects on cell proliferation and differentiation in embryonic mesenchymal cells and embryonic mouse kidneys. Since AT(2)R knock-out (KO) mice have a phenotype that is similar to that of humans with congenital renal and urinary tract anomalies (CAKUT) and develop hypertension in adulthood, these mice and wild-type controls were used for this study. Embryonic kidneys isolated from E12 to term gestation were cultured in Dulbecco's modified Eagle's medium (DMEM) with or without Ang II (10(-6) M) for 24 h ex vivo. Renal morphogenesis was histologically assessed. Mean glomerular tuft volume was determined by the method of Weibel and Gomez with the aid of image analysis software. Pax-2 and N-myc gene expression were determined by immunostaining as well as by Western blotting and real-time-quantitative polymerase chain reaction (RT-qPCR). Glomerular size was significantly smaller, and Pax-2 and N-myc expression down-regulated, in kidneys of AT(2)R KO mice compared with those of wild-type mice. In ex vivo studies, Ang II stimulated Pax-2 and N-myc mRNA expression in embryonic kidneys of wild-type mice, but this stimulatory effect was absent in embryonic kidneys of AT(2)R KO mice. Taken together, these data indicate that intrarenal AT(2)R plays an important role in nephrogenesis. Deficiency of AT(2)R may impair both Pax-2 and N-myc expression, eventually resulting in glomerular hyperfiltration that may, ultimately, lead to later development of hypertension.

Nephron Number, Uric Acid, and Renal Microvascular Disease in the Pathogenesis of Essential Hypertension

One of the world’s greatest epidemics is the epidemic of essential hypertension, which during the last 100 years has increased from a prevalence of 5% to 10% in the European and American population to >30% today. Hypertension was nonexistent in other places of the world but has risen to similar frequencies with the introduction of Western diet and culture. As a major cause of stroke, heart disease, and kidney disease, hypertension is a major underlying cause of morbidity and mortality, and therefore understanding its underlying etiology is critically important. The groundbreaking studies of Dahl and Guyton led to the recognition of the key role for the kidney in the pathogenesis, but controversy remains on the precise mechanism. The observations that several hereditary causes of hypertension result from genetic mutations that lead to increased sodium reabsorption in the nephron (particularly in the collecting duct) has led to a search for genetic causes.1 However, although genetic polymorphisms are clearly important, most studies suggest genetic mechanisms may only have a modest (20%) influence on the hypertensive phenotype.2 A congenital mechanism, or fetal programming, has also been proposed (the “Barker-Brenner hypothesis”).3,4 Low birth weights (LBWs) predispose to the later development of hypertension as well as other cardiovascular diseases, including obesity and diabetes. LBW infants often have impaired kidney development, resulting in a reduced nephron endowment. Following birth, the children have an increased risk for developing endothelial dysfunction and obesity, and by adulthood …

Plasma non-esterified fatty acids: why are we not measuring them routinely?

Non-esteri¢ed fatty acids (NEFAs), also known as free fatty acids (FFAs), are released from the hydrolysis of triglyceride in adipose tissue. Their concentration in plasma is usually in the range 100 mmol/L--1mmol/L. NEFAs are a normal part of metabolic adaptability during daily life. Their concentrations in plasma fall after eachmeal as insulin suppresses adipose tissue lipolysis, and rise during the night. As this occurs other tissues, notably skeletal muscle, adapt their substrate utilization accordingly. There is an emerging view that the ability of skeletal muscle (and possibly other tissues) to alter its metabolism appropriately for the prevailing substrate supply is associated with insulin sensitivity and good ‘metabolic health’. This capacity has been termed ‘metabolic £exibility’. A quick glance at current literature on insulin resistance, type 2 diabetes or cardiovascular disease (CVD), however, will give quite a diierent impression of the role of NEFAs. They are increasingly portrayed as the villains in a web of metabolic disturbances that link these diierent conditions in the metabolic syndrome. This view of NEFAs as ‘baddies’ could be said to start with the description of the glucose--fatty acid cycle in 1963. Over the subsequent years, elevated NEFA concentrations have been associated with impaired glucose utilization, impaired suppression of glucose production, impaired insulin secretion (although fatty acids are in fact crucial for normal insulin secretion), impaired endothelial function and vascular reactivity, accelerated hepatic very-low-density lipoprotein-triglyceride secretion, activation of cholesteryl-ester transfer protein (contributing to the dyslipidaemia of insulin resistance), and almost everything else that is bad metabolically. It is rather easy, on this basis, to make a convincing story linking elevated NEFA concentrations with most features of the metabolic syndrome, and certainly with increased risk of type 2 diabetes and CVD. NEFA concentrations are typically elevated as adipose tissue accumulates, especially with abdominal obesity. This is a tempting explanation for the many adverse eiects of abdominal obesity. If all this is true, then measurement of NEFAconcentrations should be highly informative about the risk of type 2 diabetes and CVD.Why, then, are plasma NEFA concentrations notmeasuredmore regularly in clinical practice? After all, a simple enzymatic method has been available for their measurement for several decades: we are no longer dependent upon solvent extraction and solvent-phase titration. In fact, the literature on NEFA as a risk factor is far less convincing than one might at ¢rst expect. Elevated NEFAconcentrations have been shown to be a riskmarker for the future development of type 2 diabetes in several prospective studies in various ethnic groups, but they have come out far less strongly, in fact hardly at all, as a marker for future CVD. Only in the QueŁ bec cardiovascular study were elevated NEFA concentrations found to be a risk marker for future ischaemic heart disease. In the Paris prospective study, elevated NEFA concentrations were predictive of later development of hypertension and, unexpectedly, of cancer, but not of CVD mortality. So why is it that elevated NEFA concentrations do not strongly predict CVD, other than that they have not often been measured in prospective studies? The ¢rst reason is statistical. It is similar to the reason that plasma triglyceride concentrations do not independently predict CVD risk in many studies. Plasma triglyceride concentrations are very variable from day to day in any one individual, giving a high imprecision of estimate of ‘usual’ concentration from a single fasting sample. In contrast, HDL-cholesterol concentrations, which are fairly closely inversely related to plasma triglyceride, are far more stable from day to day. Thus in a multivariate analysis, low HDL-cholesterol will appear to be a far stronger risk marker for CVD than triglyceride concentrations. The day-to-day coe⁄cient of variation of fasting plasma triglyceride concentrations is typically 20%. But for NEFA concentrations, the ¢gure is about twice that (43% in the study byWidjaja et al.). Thus, statistically, NEFA concentrations are not good markers for epidemiology. Beyond that, it is in any case unlikely that NEFA concentrations would appear as independent markers of CVD risk. As argued above, elevated NEFA concentrations are likely to be linked to CVD through other mechanisms that are themselves well-recognized risk markers, such as plasma triglyceride and lowHDL-cholesterol, impaired endothelial function, pro-thrombotic

Functional allelic heterogeneity and pleiotropy of a repeat polymorphism in tyrosine hydroxylase: Prediction of catecholamines and response to stress in twins

Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, has a common repeat polymorphism, (TCAT)n. We asked whether variation at TH influenced the autonomic stress responses in a human twin study design. Autonomic traits displayed substantial heritability (h2), up to h2=56.8±7.5% (p<0.0001) for norepinephrine secretion, and h2=61±6% (p<0.001) for heart rate. Common (TCAT)n alleles, particularly (TCAT)6 and (TCAT)10i, influenced such traits (including catecholamine secretion, as well as basal and post-stress heart rate) in allele copy number dose-dependent fashion, though in directionally opposite ways, indicating functional allelic heterogeneity. Multivariate ANOVA documented genetic pleiotropy: joint effects of the (TCAT)10i allele to influence both biochemical (norepinephrine) and physiological (heart rate) traits. (TCAT)6 allele frequencies were lower in normotensive twins at genetic risk of hypertension, consistent with an effect to protect against later development of hypertension, and suggesting that the traits predicted by these variants in still-normotensive subjects are early, heritable, “intermediate phenotypes” in the pathogenetic scheme for later development of sustained hypertension. We conclude that common allelic variation within the TH locus exerts a heritable effect on autonomic control of the circulation, and that such variation may have implications in later development of cardiovascular disease. Clinical Pharmacology & Therapeutics (2005) 77, P6–P6; doi: 10.1016/j.clpt.2004.11.025