angiotensinogen and Body-Weight

In addition to its role as an energy store, adipose tissue also acts as an endocrine organ, synthesizing and secreting hormones and cytokines. This review discusses angiotensin II (Ang-II), the biologically active component of the renin-angiotensin system (RAS). Evidence suggests that a functioning RAS is present in adipose tissue. Animal studies have demonstrated that modifying the amount of Ang-II in the body (eg, using RAS knockout/transgenic animal models or the pharmacological treatment of animal models to prevent the formation or action of Ang-II) directly influences body weight and adiposity. In humans, body fat is correlated with levels of angiotensinogen, a precursor of Ang-II. Thus, the treatment of obesity could be improved through the use of substances that interfere with Ang-II.

Topics: Adipose Tissue; Adiposity; Angiotensin II; Angiotensinogen; Animals; Body Weight; Disease Models, Animal; Humans; Obesity; Receptors, Angiotensin; Renin-Angiotensin System

The main purpose of this randomized controlled study was to assess the effects of postmenopausal estrogen replacement therapy on blood pressure (BP) and plasma renin substrate (PRS) in non insulin-dependent diabetic patients (DNID). We randomized 32 postmenopausal DNID (mean age: 55.3 +/- 4.2 years) into two groups: 16 women were untreated, and 16 received percutaneous estradiol (E2) 17 beta and natural progesterone for 6 months. Systolic (SBP) and diastolic (DBP) blood pressure were monitored by an automatic device at inclusion and on the 1st, 3rd and 6th months of therapy. Treatment efficacy was proven by significant E2 plasma increase to 92.2 +/- 13.4 pg/ml in the treated group, which is a sufficient level for preventing postmenopausal osteoporosis. No significant inter or or intra-individual variation in SBP or DBP was observed in either group. The same stability was noted for plasma renin substrate. No significant difference was noted between the two groups in terms of body weight, fructosamine and glycosylated hemoglobin A1c after 1, 3 and 6 months. There was also no change in plasma levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and apolipoproteins A1 and B. All the patients who received replacement therapy wished to continue treatment. We conclude that the association of percutaneous E2 17 beta and natural progesterone had no deleterious effects, in diabetic patients, on BP, carbohydrate and lipoprotein metabolism. Thus this postmenopausal replacement therapy appears preferable in this vascular high risk population, particularly since estrogens via the parenteral route may have an antiatherogenic effect by direct action on the vessel walls.

Topics: Administration, Cutaneous; Administration, Oral; Angiotensinogen; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Estradiol; Female; Humans; Lipoproteins; Menopause; Middle Aged; Progesterone

The aim of this study was to compare the metabolic effects of two presentations of 17 beta-oestradiol (E2) which are of recognized effectiveness in the prevention of post-menopausal bone loss, one being administered via the oral and the other via the percutaneous route. During this prospective, randomized study, 32 patients were treated for 2 mth with either 2 mg/day of oral micronized E2 (n = 16) or 1.5-3 mg/day of percutaneous E2 (n = 16). Both regimens proved efficacious, since significant increases in oestrone (E1) and E2 concentrations ranging up to mid-follicular values were observed. In the percutaneous-treatment group we noted a significant decrease in triglycerides (TG), without any significant changes in high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C). In the oral-treatment group, we saw no significant increase in HDL-C, although significant increases were observed in body weight, TG, plasma renin substrate (PRS) and sex-hormone-binding globulin (SHBG) as well as significant decreases in antithrombin III (AT III) activity and antigen. All of these metabolic variations led us to the conclusion that oral E2 at the dose established as effective in preventing post-menopausal osteoporosis may, even when micronized, alter certain metabolic and haemostatic parameters in a population characterized by increases in cardiovascular risk factors and morbidity. Oral oestrogen replacement therapy should therefore continue to be used only in carefully selected patients and be strictly followed up by systematic checks on a series of metabolic criteria.

Topics: Administration, Cutaneous; Administration, Oral; Angiotensinogen; Body Weight; Estradiol; Estrogen Replacement Therapy; Female; Humans; Lipoproteins; Osteoporosis, Postmenopausal; Prospective Studies; Randomized Controlled Trials as Topic; Sex Hormone-Binding Globulin

This study aimed to investigate the effect of combination of high-salt intake and hypertension on renal functional and histological damage, associated with renal (pro)renin receptor [(P)RR] and AT1 receptor in rats.. Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received regular rat chow (normal-salt diet 0.9%) or high-salt rat chow (high-salt diet 8.9%) for 6 weeks from 6 to 12 weeks of age. Systolic blood pressure, serum creatinine and blood urea nitrogen (BUN) were measured. Histological analysis of the kidney was performed. Western blot analysis was performed on the expressions of (P)RR, angiotensinogen and AT1 receptor in the kidney.. High-salt intake significantly increased systolic blood pressure in WKYs and especially in SHRs. High-salt intake significantly increased serum creatinine and BUN, and accelerated renal tubulointerstitial fibrosis and glomerular sclerosis in SHRs. High-salt intake significantly enhanced the renal tissue expressions of (P)RR, angiotensinogen and AT1 receptor in SHRs.. High-salt intake accelerates functional and histological renal damage associated with renal tissue overexpression of (P)RR and AT1 receptors in SHRs.

Topics: Angiotensinogen; Animals; Blood Pressure; Blood Urea Nitrogen; Body Weight; Creatinine; Fibrosis; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney; Male; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Prorenin Receptor; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Signal Transduction; Sodium Chloride, Dietary; Systole

In angiotensin II (ANG II)-dependent hypertension, there is an angiotensin type 1 receptor-dependent amplification mechanism enhancing intrarenal angiotensinogen (AGT) formation and secretion in the tubular fluid. To evaluate the role of increased arterial pressure, AGT mRNA, protein expression, and urinary AGT (uAGT) excretion and tissue injury were assessed in both kidneys of two-kidney, one-clip Sprague-Dawley hypertensive rats subjected to left renal arterial clipping (0.25-mm gap). By 18-21 days, systolic arterial pressure increased to 180 ± 3 mmHg, and uAGT increased. Water intake, body weights, 24-h urine volumes, and sodium excretion were similar. In separate measurements of renal function in anesthetized rats, renal plasma flow and glomerular filtration rate were similar in clipped and nonclipped kidneys and not different from those in sham rats, indicating that the perfusion pressure to the clipped kidneys remained within the autoregulatory range. The nonclipped kidneys exhibited increased urine flow and sodium excretion. The uAGT excretion was significantly greater in nonclipped kidneys compared with clipped and sham kidneys. AGT mRNA was 2.15-fold greater in the nonclipped kidneys compared with sham (1.0 ± 0.1) or clipped (0.98 ± 0.15) kidneys. AGT protein levels were also greater in the nonclipped kidneys. The nonclipped kidneys exhibited greater glomerular expansion and immune cell infiltration, medullary fibrosis, and cellular proliferation than the clipped kidneys. Because both kidneys have elevated ANG II levels, the greater tissue injury in the nonclipped kidneys indicates that an increased arterial pressure synergizes with increased intrarenal ANG II to stimulate AGT production and exert greater renal injury.

Topics: Angiotensinogen; Animals; Arterial Pressure; Body Weight; Drinking; Fibrosis; Hypertension, Renovascular; Immunity, Cellular; Kidney; Kidney Glomerulus; Kidney Medulla; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium

It has not yet been fully elucidated whether cardiac tissue levels of prorenin, renin and (P)RR are activated in hypertension with a high salt intake. We hypothesized that a high salt intake activates the cardiac tissue renin angiotensin system and prorenin-(pro)renin receptor system, and damages the heart at an early stage of hypertension.. Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) received regular (normal-salt diet, 0.9%) and high-salt (8.9%) chow for 6 weeks from 6 to 12 weeks of age. The systolic blood pressure, plasma renin activity (PRA) and plasma angiotensin II concentration were measured, and the protein expressions of prorenin, (pro)renin receptor, angiotensinogen, angiotensin II AT1 receptor, ERK1/2, TGF-β, p38MAPK and HSP27 in the myocardium were investigated. The cardiac function was assessed by echocardiography, and histological analysis of the myocardium was performed.. The high-salt diet significantly increased the systolic blood pressure, and significantly reduced the PRA and plasma angiotensin II concentration both in the WKYs and SHRs. Cardiac expressions of prorenin, renin, (P)RR, angiotensinogen, angiotensin II AT1 receptor, phosphorylated (p)-ERK1/2, p-p38MAPK, TGF-β and p-HSP27 were significantly increased by the high salt diet both in the WKYs and SHRs. The high-salt diet significantly increased the interventricular septum thickness and cardiomyocyte size, and accelerated cardiac interstitial and perivascular fibrosis both in the WKYs and SHRs. On the other hand, dilatation of left ventricular end-diastolic dimension and impairment of left ventricular fractional shortening was shown only in salt loaded SHRs.. The high-salt diet markedly accelerated cardiac damage through the stimulation of cardiac (P)RR and angiotensin II AT1 receptor by increasing tissue prorenin, renin and angiotensinogen and the activation of ERK1/2, TGF-β, p38MAPK and HSP27 under higher blood pressure.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Body Weight; Echocardiography; Gene Expression; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Heart Ventricles; HSP27 Heat-Shock Proteins; Hypertension; Lung; Male; Myocardium; Organ Size; p38 Mitogen-Activated Protein Kinases; Prorenin Receptor; Rats; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Renin; Signal Transduction; Sodium Chloride, Dietary; Transforming Growth Factor beta1

Urinary angiotensinogen is considered a reliable biomarker for intrarenal renin-angiotensin system activity. The aims of this study were to assess the urinary angiotensinogen level during the first day of life and to evaluate its correlation with renal function in critically ill neonates.. Urinary angiotensinogen concentration during the first 24 hours of life was measured in 98 critically ill neonates. Neonatal renal function was assessed by urinary levels of cystatin-C, albumin and α1-microglobulin and urinary electrolyte excretion.. Urinary angiotensinogen level decreased with increasing gestational age and body weight in critically ill neonates (P<0.001). After adjustment for gestational age, urinary angiotensinogen level correlated with urinary fractional excretion of sodium and urinary levels of cystatin-C and α1-microglobulin. Multivariate linear regression identified a significant impact of urinary cystatin-C on urinary angiotensinogen level (P<0.001). Furthermore, urinary angiotensinogen was significantly increased in neonates with a urinary cystatin-C-to-creatinine ratio ⩾2500 ng/mg, which was the optimal cut-off value to predict acute kidney injury in our previous study.. The urinary angiotensinogen level correlates with the overall maturity of renal function during the early postnatal period in critically ill neonates and an increased urinary angiotensinogen level might reflect renal injury in immature neonates.

Topics: Albuminuria; Alpha-Globulins; Angiotensinogen; Body Weight; Creatinine; Critical Illness; Cystatin C; Electrolytes; Gestational Age; Humans; Infant, Newborn; Linear Models; Multivariate Analysis; Potassium; Sodium

We recently demonstrated that adipocyte deficiency of angiotensinogen (AGT) ablated high-fat diet-induced elevations in plasma angiotensin II (Ang II) concentrations and obesity-hypertension in male mice. Hepatocytes are the predominant source of systemic AGT. Therefore, in this study, we defined the contribution of hepatocyte-derived AGT to obesity-induced elevations in plasma AGT concentrations and hypertension. Male Agt(fl/fl) mice expressing albumin-driven Cre recombinase were bred to female Agt(fl/fl) mice to generate Agt(fl/fl) or hepatocyte AGT-deficient male mice (Agt(Alb)). Mice were fed a low-fat or high-fat diet for 16 weeks. Hepatocyte AGT deficiency had no significant effect on body weight. Plasma AGT concentrations were increased in obese Agt(fl/fl) mice. Hepatocyte AGT deficiency markedly reduced plasma AGT and Ang II concentrations in lean and obese mice. Moreover, hepatocyte AGT deficiency reduced the content and release of AGT from adipose explants. Systolic blood pressure was markedly decreased in lean (by 18 mm Hg) and obese Agt(Alb) mice (by 54 mm Hg) compared with Agt(fl/fl) controls. To define mechanisms, we quantified effects of Ang II on mRNA abundance of megalin, an AGT uptake transporter, in 3T3-L1 adipocytes. Ang II stimulated adipocyte megalin mRNA abundance and decreased media AGT concentrations. These results demonstrate that hepatocytes are the predominant source of systemic AGT in both lean and obese mice. Moreover, reductions in plasma angiotensin concentrations in obese hepatocyte AGT-deficient mice may have limited megalin-dependent uptake of AGT into adipocytes for the production of Ang II in the development of obesity-hypertension.

Topics: Angiotensinogen; Animals; Blood Pressure; Body Weight; Cells, Cultured; Disease Models, Animal; Female; Gene Expression Regulation; Hepatocytes; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; RNA, Messenger; Thinness

We have previously reported that intrarenal angiotensin II (Ang II) levels are increased long before diabetes becomes apparent in obese Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of type 2 diabetes. In this study, we examined the changes in intrarenal renin-angiotensin system (RAS) activity in the developing kidneys of OLETF rats. Ang II contents and mRNA levels of RAS components were measured in male OLETF and control Long-Evans Tokushima (LETO) rats at postnatal days (PND) 1, 5, and 15, and at 4-30 weeks of age. In both LETO and OLETF rats, kidney Ang II levels peaked at PND 1, then decreased during the pre- and post-weaning periods. However, Ang II levels and gene expression of RAS components, including angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), were not significantly different between LETO and OLETF rats. Intrarenal Ang IIcontents further decreased during puberty (from 7 to 11 weeks of age) in LETO rats, bur not in OLETF rats. At 11 weeks of age, kidney Ang II levels, urinary AGT excretion, and mRNA levels of AGT and renin were higher in OLETF rats than in LETO rats, while blood glucose levels were not significantly different between these groups of rats. These data indicate that continued intrarenal expression of Ang II during pubescence contributes to the increases in intrarenal Ang II levels in prediabetic OLETF rats, and is associated with increased intrarenal AGT and renin expression. Inappropriate activation of the intrarenal RAS in the prediabetic stage may facilitate the onset and development of diabetic nephropathy in later life.

Topics: Albuminuria; Angiotensin II; Angiotensinogen; Animals; Blood Glucose; Blood Pressure; Body Weight; Collagen; Connective Tissue Growth Factor; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Female; Gene Expression Regulation; Kidney; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred OLETF; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Time Factors; Transforming Growth Factor beta

It has been suggested that proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, may function as a component of the tissue renin-angiotensin system (RAS). To investigate the role of proang-12 in the production of angiotensin II (Ang II), we measured its plasma and tissue concentrations in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, with and without RAS inhibition. The 15-week-old male WKY and SHR rats were left untreated or were treated for 7 days with 30 mg kg(-1) per day losartan, an angiotensin receptor blocker, or with 20 mg kg(-1) per day imidapril, an angiotensin-converting enzyme (ACE) inhibitor. Both treatments increased renin activity and the concentrations of angiotensin I (Ang I) and Ang II in the plasma of WKY and SHR rats, but neither affected plasma proang-12 levels. In contrast to the comparatively low level of proang-12 seen in plasma, cardiac and renal levels of proang-12 were higher than those of Ang I and Ang II. In addition, despite activation of the RAS in the systemic circulation, tissue concentrations of proang-12 were significantly reduced following treatment with losartan or imidapril. Similar reductions were also observed in the tissue concentrations of Ang II in both strains, without a reduction in Ang I. These results suggest that tissue concentrations of proang-12 and Ang II are regulated independently of the systemic RAS in WKY and SHR rats, which is consistent with the notion that proang-12 is a component of only the tissue RAS.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Body Weight; Imidazolidines; Kidney; Losartan; Male; Myocardium; Organ Size; Peptide Fragments; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Renin-Angiotensin System

Previous studies demonstrated that overexpression of angiotensinogen (AGT) in adipose tissue increased blood pressure. However, the contribution of endogenous AGT in adipocytes to the systemic renin-angiotensin system (RAS) and blood pressure control is undefined. To define a role of adipocyte-derived AGT, mice with loxP sites flanking exon 2 of the AGT gene (Agt(fl/fl)) were bred to transgenic mice expressing Cre recombinase under the control of an adipocyte fatty acid-binding protein 4 promoter (aP2) promoter to generate mice with adipocyte AGT deficiency (Agt(aP2)). AGT mRNA abundance in adipose tissue and AGT secretion from adipocytes were reduced markedly in adipose tissues of Agt(aP2) mice. To determine the contribution of adipocyte-derived AGT to the systemic RAS and blood pressure control, mice were fed normal laboratory diet for 2 or 12 mo. In males and females of each genotype, body weight and fat mass increased with age. However, there was no effect of adipocyte AGT deficiency on body weight, fat mass, or adipocyte size. At 2 and 12 mo of age, mice with deficiency of AGT in adipocytes had reduced plasma concentrations of AGT (by 24-28%) compared with controls. Moreover, mice lacking AGT in adipocytes exhibited reduced systolic blood pressures compared with controls (Agt(fl/fl), 117 ± 2; Agt(aP2), 110 ± 2 mmHg; P < 0.05). These results demonstrate that adipocyte-derived AGT contributes to the systemic RAS and blood pressure control.

Topics: Adipocytes; Adiposity; Angiotensinogen; Animals; Blood Glucose; Blood Pressure; Body Weight; Female; Male; Mice; Mice, Transgenic; Renin-Angiotensin System

Adaptive growth responses of the embryo and fetus to nutritional restraint are important in ensuring early survival, but they are implicated in the programming of hypertension. It has been demonstrated that kidney growth and nephrogenesis are each regulated by intrarenal factors, including the insulin-like growth factors, glucocorticoids, and the renin-angiotensin system. Therefore, we have investigated the impact of periconceptional undernutrition (PCUN; from approximately 6 wk before to 7 days after conception) in singleton (control, n = 18; PCUN, n = 16) and twin pregnancies (control, n = 6; PCUN, n = 5) on the renal mRNA expression of 11beta- hydroxysteroid dehydrogensase type 1 and type 2 (11beta-HSD-1 and -2), the glucocorticoid (GR), and mineralocorticoid receptors, angiotensinogen, angiotensin receptor type 1 (AT1R) and 2 (AT2R), IGF-1 and IGF-2, and IGF1R and IGF2R at approximately 55 days gestation. There was no effect of PCUN or fetal number on fetal weight on relative kidney weight at approximately day 55 of gestation. There was an inverse relationship between the relative weight of the fetal kidney at approximately day 55 and maternal weight loss during the periconceptional period in fetuses exposed to PCUN. Exposure to PCUN resulted in a higher expression of IGF1 in the fetal kidney in singleton and twin pregnancies. Being a twin resulted in higher intrarenal expression of IGF-1 and IGF-2, GR, angiotensinogen, AT1R, and AT2R mRNA at 55 days gestation. Renal 11beta-HSD-2 mRNA expression was higher in PCUN singletons, but not PCUN twins, compared with controls. Thus, there may be an adaptive response in the kidney to the early environment of a twin pregnancy, which precedes the fetal growth restriction that occurs later in pregnancy. The kidney of the twin fetus exposed to periconceptional undernutrition may also be less protected from the consequences of glucocorticoid exposure.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Angiotensinogen; Animals; Body Weight; Female; Gene Expression Regulation, Developmental; Gestational Age; Hypertension, Renal; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Kidney; Malnutrition; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Glucocorticoid; RNA, Messenger; Sheep; Twins

Previous studies have demonstrated that the urinary excretion of angiotensinogen is significantly increased in ANG II-infused hypertensive rats, which is associated with an augmentation of intrarenal ANG II levels. These findings suggest that urinary angiotensinogen excretion rates provide an index of intrarenal ANG II levels in ANG II-dependent hypertensive states. However, little information is available regarding the urinary excretion of angiotensinogen in ANG II-dependent malignant hypertension.. This study was performed to determine if urinary angiotensinogen excretion is increased in Cyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1aRen2)] with inducible ANG II-dependent malignant hypertension. Adult male Cyp1a1-Ren2 rats (n = 6) were fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days to induce ANG II-dependent malignant hypertension.. Rats induced with I3C exhibited pronounced increases in systolic blood pressure (208 ± 7 versus 127 ± 3 mm Hg; P < 0.001), marked proteinuria (29.4 ± 3.6 versus 5.9 ± 0.3 mg/d; P < 0.001) and augmented urinary angiotensinogen excretion (996 ± 186 versus 241 ± 31 ng/d; P < 0.01). Chronic administration of the AT₁ receptor antagonist, candesartan (25 mg/L in drinking water, n = 6), prevented the I3C-induced increases in systolic blood pressure (125 ± 5 mm Hg; P < 0.001), proteinuria (7.3 ± 1.0 mg/d; P < 0.001) and urinary angiotensinogen excretion (488 ± 51 ng/d, P < 0.01).. These data demonstrate that the urinary excretion of angiotensinogen is markedly augmented in ANG II-dependent malignant hypertension. Such increased urinary angiotensinogen excretion may contribute to augmented intrarenal ANG II levels and, thereby, to the increased blood pressure in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Cytochrome P-450 CYP1A1; Humans; Hypertension, Malignant; Male; Middle Aged; Rats; Rats, Transgenic; Renin; Tetrazoles

ATRAP [ANG II type 1 receptor (AT1R)-associated protein] is a molecule which directly interacts with AT1R and inhibits AT1R signaling. The aim of this study was to examine the effects of continuous ANG II infusion on the intrarenal expression and distribution of ATRAP and to determine the role of AT1R signaling in mediating these effects. C57BL/6 male mice were subjected to vehicle or ANG II infusions at doses of 200, 1,000, or 2,500 ng·kg(-1)·min(-1) for 14 days. ANG II infusion caused significant suppression of ATRAP expression in the kidney but did not affect ATRAP expression in the testis or liver. Although only the highest ANG II dose (2,500 ng·kg(-1)·min(-1)) provoked renal pathological responses, such as an increase in the mRNA expression of angiotensinogen and the α-subunit of the epithelial sodium channel, ANG II-induced decreases in ATRAP were observed even at the lowest dose (200 ng·kg(-1)·min(-1)), particularly in the outer medulla of the kidney, based on immunohistochemical staining and Western blot analysis. The decrease in renal ATRAP expression by ANG II infusion was prevented by treatment with the AT1R-specific blocker olmesartan. In addition, the ANG II-mediated decrease in renal ATRAP expression through AT1R signaling occurred without an ANG II-induced decrease in plasma membrane AT1R expression in the kidney. On the other hand, a transgenic model increase in renal ATRAP expression beyond baseline was accompanied by a constitutive reduction of renal plasma membrane AT1R expression and by the promotion of renal AT1R internalization as well as the decreased induction of angiotensinogen gene expression in response to ANG II. These results suggest that the plasma membrane AT1R level in the kidney is modulated by intrarenal ATRAP expression under physiological and pathophysiological conditions in vivo.

Topics: Adaptor Proteins, Signal Transducing; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Body Weight; Cell Membrane; Epithelial Sodium Channels; Immunohistochemistry; Kidney; Kidney Medulla; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NADPH Oxidase 4; NADPH Oxidases; Reverse Transcriptase Polymerase Chain Reaction

Increased angiotensinogen (AGT) production by white adipose tissue has been related to not only obesity but also hypertension. Several studies have highlighted the importance of the angiotensin II type 2 receptor (AT2) in the regulation of blood pressure and fat mass, but the relevance of this transporter in a physiopathological model of increased AGT production, as it occurs in obesity, has not yet been investigated. We used transgenic mice that display either a deletion of AT2 (AT2 KO), an overexpression of AGT (OVEX), or both compound mutants (KOVEX). Results demonstrated that adipocyte hypertrophy and increased lipogenic gene expression induced by adipose AGT overproduction was rescued by deletion of AT2. In line with AGT overexpression, KOVEX and OVEX mice have similar increased plasma AGT levels. However, KOVEX mice display a higher blood pressure than OVEX mice. In kidney, renin expression was clearly reduced in OVEX mice, and its expression was normalized in KOVEX mice. Taken together, we demonstrated that the loss of AT2 expression was sufficient to rescue obesity induced by adipose tissue AGT overexpression and confirmed the necessary role of AT2 for the onset of obesity in this model. Furthermore, despite a reduction of adipose mass in KOVEX, AT2 deficiency caused increased renin production, further worsening the hypertension caused by AGT overexpression.

Topics: Adipose Tissue; Adiposity; Angiotensinogen; Animals; Body Weight; Cell Count; Cells, Cultured; Female; Genotype; Hypertension; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Receptor, Angiotensin, Type 2

Blood pressure (BP) is more salt sensitive in men than in premenopausal women. In Dahl salt-sensitive rats (DS), high-salt (HS) diet increases BP more in males than females. In contrast to the systemic renin-angiotensin system, which is suppressed in response to HS in male DS, intrarenal angiotensinogen expression is increased, and intrarenal levels of ANG II are not suppressed. In this study, the hypothesis was tested that there is a sexual dimorphism in HS-induced upregulation of intrarenal angiotensinogen mediated by testosterone that also causes increases in BP and renal injury. On a low-salt (LS) diet, male DS had higher levels of intrarenal angiotensinogen mRNA than females. HS diet for 4 wk increased renal cortical angiotensinogen mRNA and protein only in male DS, which was prevented by castration. Ovariectomy of female DS had no effect on intrarenal angiotensinogen expression on either diet. Radiotelemetric BP was similar between males and castrated rats on LS diet. HS diet for 4 wk caused a progressive increase in BP, protein and albumin excretion, and glomerular sclerosis in male DS rats, which were attenuated by castration. Testosterone replacement in castrated DS rats increased BP, renal injury, and upregulation of renal angiotensinogen associated with HS diet. Testosterone contributes to the development of hypertension and renal injury in male DS rats on HS diet possibly through upregulation of the intrarenal renin-angiotensin system.

Topics: Albuminuria; Angiotensinogen; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Drug Implants; Estradiol; Female; Hypertension; Kidney; Male; Orchiectomy; Ovariectomy; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Sex Factors; Sodium Chloride, Dietary; Telemetry; Testosterone; Time Factors; Up-Regulation

Angiotensin-(1-12) [ANG-(1-12)] is a newly identified peptide detected in a variety of rat tissues, including the brain. To determine whether brain ANG-(1-12) participates in blood pressure regulation, we treated male adult (mRen2)27 hypertensive rats (24-28 wk of age) with Anti-ANG-(1-12) IgG or Preimmune IgG via an intracerebroventricular cannula for 14 days. Immunoneutralization of brain ANG-(1-12) lowered systolic blood pressure (-43 +/- 8 mmHg on day 3 and -26 +/- 7 mmHg on day 10 from baseline, P < 0.05). Water intake was lower on intracereroventricular day 6 in the Anti-ANG-(1-12) IgG group, accompanied by higher plasma osmolality on day 13, but there were no differences in urine volume, food intake, or body weight during the 2-wk treatment. In Preimmune IgG-treated animals, there were no significant changes in these variables over the 2-wk period. The antihypertensive effects produced by endogenous neutralization of brain ANG-(1-12) suggest that ANG-(1-12) is functionally active in brain pathways regulating blood pressure.

Topics: Angiotensinogen; Angiotensins; Animals; Blood Pressure; Body Weight; Brain; Disease Models, Animal; Drinking; Eating; Hypertension; Immunoglobulin G; Infusion Pumps, Implantable; Male; Osmolar Concentration; Peptide Fragments; Rats; Rats, Transgenic; Renin; Time Factors; Urodynamics

We reported previously that targeted expression of rat prorenin to the liver under the control of the human alpha1-antitrypsin promoter increased plasma prorenin levels by several-hundred-fold in male transgenic rats and caused cardiac hypertrophy, severe renal lesions, and myocardial fibrosis by 20 weeks of age, despite normal blood pressure. We examined the evolution of the phenotype of male transgenic rats over 12 months and the effects of binephrectomy on the renin-angiotensin (Ang) system. Plasma prorenin levels were >1000-fold higher than in wild type littermates, whereas plasma and renal Ang II levels were no different from wild-type (WT) levels, and kidney renin levels were suppressed in transgenic rats. In contrast to our earlier report, transgenic rats had increased systolic blood pressure at 3 to 12 months of age, and only modest renal lesions and myocardial fibrosis were evident after 6 months of age. Binephrectomy reduced plasma renin activity and concentration and prorenin levels by 50% to 80% and Ang II levels by 90% in WT rats. By contrast, binephrectomy increased plasma renin activity and concentration and prorenin levels by 52.0-, 13.0-, and 5.8-fold, respectively, without change in Ang II levels in transgenic rats. We conclude that, in the animals studied in this report, elevated prorenin levels did not cause renal lesions or myocardial fibrosis during the first 6 months of age. Ang peptide formation consequent to the increased prorenin levels prevented reduction of Ang II levels after binephrectomy and was likely to have contributed to hypertension, cardiac hypertrophy, and suppression of kidney renin levels in these transgenic rats.

Topics: alpha 1-Antitrypsin; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Body Weight; Humans; Hypertension, Renal; Hypertrophy, Left Ventricular; Kidney; Liver; Male; Myocardium; Nephrectomy; Organ Size; Rats; Rats, Inbred F344; Rats, Transgenic; Renin; Transgenes

The objectives of this study were to determine the effects of chronic angiotensin II (ANG II) infusions on ANG II content and angiotensinogen expression in the mouse kidney and the role of the angiotensin II type 1 receptor (AT(1)R) in mediating these changes. C57BL/6J male mice were subjected to ANG II infusions at doses of 400 or 1,000 ng.kg(-1).min(-1) either alone or with an AT(1)R blocker (olmesartan; 3 mg.kg(-1).day(-1)) for 12 days. Systolic and mean arterial pressures were determined by tail-cuff plethysmography and radiotelemetry. On day 13, blood and kidneys were collected for ANG II determinations by radioimmunoanalysis and intrarenal angiotensinogen expression studies by quantitative RT-PCR, Western blotting, and immunohistochemistry. ANG II infusions at the low dose elicited progressive increases in systolic blood pressure (135 +/- 2.5 mmHg). In contrast, the high dose induced a rapid increase (152 +/- 2.5, P < 0.05 vs. controls, 109 +/- 2.8). Renal ANG II content was increased by ANG II infusions at the low dose (1,203 +/- 253 fmol/g) and the high dose (1,258 +/- 173) vs. controls (499 +/- 40, P < 0.05). Kidney angiotensinogen mRNA and protein were increased only by the low dose to 1.13 +/- 0.02 and 1.26 +/- 0.10, respectively, over controls (1.00, P < 0.05). These effects were not observed in mice infused at the high dose and those receiving olmesartan. The results indicate that chronic ANG II infusions augment mouse intrarenal ANG II content with AT(1)R-dependent uptake occurring at both doses, but only the low dose of infusion, which elicited a slow progressive response, causes an AT(1)R-dependent increase in intrarenal angiotensinogen expression.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Body Weight; Hypertension; Kidney; Male; Mice; Mice, Inbred C57BL; Organ Size; Receptor, Angiotensin, Type 1; Renin

In transgenic rats, TGR(ASrAOGEN)680, with reduced glial expression of angiotensinogen, changes in brain angiotensinogen are associated with reductions in serotonin (5-HT) content and/or 5-HT metabolism as determined in various brain regions, including the hypothalamus. These rats showed an anxious phenotype upon a first behavioural screen. The present study aimed to extend the search for functional consequences of changes in brain 5-HT with respect to feeding behaviour in these transgenic rats. In feeding experiments, rats were treated with the anorectic drug fenfluramine to probe for functional changes in the serotonergic satiety system. Fenfluramine (0.3 mg/kg, i.p.) reduced food intake in TGR(ASrAOGEN)680 rats whereas the minimal effective dose in wild-type rats was 3 mg/kg, i.p. Although, in the cortex, no differences were apparent in the expression of serotonin 5-HT(1A), 5-HT(1B), 5-HT(2C) receptor and 5-HT transporter mRNAs between TGR(ASrAOGEN)680 and wild-type rats, the expression of mRNAs for the 5-HT(2C) receptor and 5-HT transporter mRNA were significantly higher in the hypothalamus of TGR(ASrAOGEN)680 rats compared to wild-type rats. No differences were found in the mRNA levels for hypothalamic 5-HT(1A) and 5-HT(1B) receptors between TGR(ASrAOGEN)680 and wild-type rats. Taken together, these findings suggest that the transgenic effect on the brain 5-HT system is paralleled by functional changes of the serotonergic feeding system.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Body Weight; Brain; Cerebral Cortex; Eating; Feeding Behavior; Fenfluramine; Hypothalamus; Male; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; RNA, Messenger; Satiety Response; Serotonin; Serotonin Agents; Serotonin Plasma Membrane Transport Proteins

Substantial evidence suggests that the intrarenal renin-angiotensin system (RAS) plays a role in the pathogenesis of diabetic nephropathy. Although the glomerular RAS is activated in the streptozotocin (STZ)-diabetic rat, the status of the glomerular RAS in the Zucker diabetic fatty (ZDF) rat, which is a commonly used genetic model of diabetes, is not known. Angiotensinogen (AGT), angiotensin II (Ang II), angiotensin converting enzyme (ACE), and angiotensin converting enzyme 2 (ACE2) were measured in glomeruli isolated from 4-week-old STZ-diabetic rats and 32-week-old ZDF rats. Glomerular injury was evaluated by histopathologic methods. Both STZ-diabetic and ZDF rats exhibited marked hyperglycemia and renal hypertrophy, but only ZDF rats demonstrated proteinuria and glomerulosclerosis. Glomerular AGT and Ang II levels were increased significantly in STZ-diabetic compared with nondiabetic control rats, accompanied by a reduction in ACE2 activity. In contrast, glomerular AGT, Ang II, and ACE2 were similar in ZDF rats and lean controls. ACE levels were not affected by diabetes in either diabetic model. In conclusion, the glomerular RAS is activated in the STZ diabetic rat but not in the ZDF rat despite a similar degree of hyperglycemia. The mechanism of nephropathy in the ZDF rat may involve factors other than hyperglycemia and RAS activation, such as hypertension and hyperlipidemia.

Topics: Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Body Weight; Diabetes Mellitus, Experimental; Kidney Glomerulus; Male; Obesity; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Rats, Zucker; Renin-Angiotensin System; Streptozocin

We recently demonstrated that renin-angiotensin system (RAS) overactivity during late gestation in rats is associated with increased kidney and urine levels of ANG-(1-7) and enhanced kidney immunostaining of ANG-(1-7) and angiotensin-converting enzyme 2 (ACE2). To understand the temporal-spatial changes in normal and hypertensive pregnancies, the renal distribution of ANG-(1-7) and ACE2 in association with kidney angiotensin peptides and ACE2 activity was examined in virgin, normal pregnant (NP; gestational days 5, 15, and 19) and reduced uterine perfusion pressure (RUPP at day 19) pregnant Sprague-Dawley rats. ANG-(1-7) and ACE2 immunocytochemical staining increased 1.8- and 1.9-fold and 1.7- and 1.8-fold, respectively, at days 15 and 19 of NP, compared with virgin rats. ANG-(1-7) and ANG II concentrations were increased in the kidney at 19 days of gestation. ACE2 activity measured using a fluorescent substrate was increased 1.9- and 1.9-fold in the cortex and 1.9- and 1.8-fold in the medulla at days 15 and 19 of NP. In the RUPP animals, ANG-(1-7) immunostaining and concentration were significantly decreased compared with 19-day NP rats. ACE2 activity was unchanged in the cortex and medulla of RUPP rats. In conclusion, during NP, the concurrent changes of ACE2 and ANG-(1-7) suggest that ACE2 plays an important role in regulating the renal levels of ANG-(1-7) at mid to late gestation. However, the decrease in renal ANG-(1-7) content in the absence of a concomitant decrease in ACE2 implicates the participation of other ANG-(1-7) forming or degrading enzymes during hypertensive pregnancy.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Blood Pressure; Body Weight; Estradiol; Female; Fluorescent Antibody Technique; Hypertension, Pregnancy-Induced; Immunohistochemistry; Kidney; Peptide Fragments; Peptidyl-Dipeptidase A; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Proteinuria; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Renin; Urodynamics; Uterus

Reduced uterine perfusion initiated in late gestation in the rat results in intrauterine growth restriction (IUGR) and development of hypertension by 4 wk of age. We hypothesize that the renin angiotensin system (RAS), a regulatory system important in the long-term control of blood pressure, may be programmed by placental insufficiency and may contribute to the etiology of IUGR hypertension. We previously reported that RAS blockade abolished hypertension in adult IUGR offspring; however, the mechanisms responsible for the early phase of hypertension are unresolved. Therefore, the purpose of this study was to examine RAS involvement in early programmed hypertension and to determine whether temporal changes in RAS expression are observed in IUGR offspring. Renal renin and angiotensinogen mRNA expression were significantly decreased at birth (80 and 60%, respectively); plasma and renal RAS did not differ in conjunction with hypertension (mean increase of 14 mmHg) in young IUGR offspring; however, hypertension (mean increase of 22 mmHg) in adult IUGR offspring was associated with marked increases in renal angiotensin-converting enzyme (ACE) activity (122%) and renal renin and angiotensinogen mRNA (7-fold and 7.4-fold, respectively), but no change in renal ANG II or angiotensin type 1 receptor. ACE inhibition (enalapril, 10 mg x kg(-1) x day(-1), administered from 2 to 4 wk of age) abolished hypertension in IUGR at 4 wk of age (decrease of 15 mmHg, respectively) with no significant depressor effect in control offspring. Therefore, temporal alterations in renal RAS are observed in IUGR offspring and may play a key role in the etiology of IUGR hypertension.

Topics: Angiotensinogen; Animals; Birth Weight; Blood Pressure; Body Weight; Female; Hypertension; Kidney; Male; Peptidyl-Dipeptidase A; Placental Insufficiency; Pregnancy; Rats; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; RNA, Messenger; Sex Factors

Previous studies have shown that intrauterine growth restriction (IUGR) can impair nephrogenesis, but uncertainties remain about the importance of the gestational timing of the insult and the effects on the renal renin-angiotensin system (RAS). We therefore hypothesized that induction of IUGR during late gestation alters the RAS, and this is associated with a decrease in nephron endowment. Our aims were to determine the effects of IUGR induced during the later stages of nephrogenesis on 1) nephron number; 2) mRNA expression of angiotensin AT(1) and AT(2) receptors, angiotensinogen, and renin genes in the kidney; and 3) the size of maculae densae. IUGR was induced in fetal sheep (n = 7) by umbilical-placental embolization from 110 to 130 days of the approximately 147-day gestation; saline-infused fetuses served as controls (n = 7). Samples of cortex from the left kidney were frozen, and the right kidney was perfusion fixed. Total kidney volume, nephron number, renal corpuscle volume, total maculae densae volume, and the volume of macula densa per glomerulus were stereologically estimated. mRNA expression of AT(1) and AT(2) receptors, angiotensinogen, and renin in the renal cortex was determined. In IUGR fetuses at 130 days, body and kidney weights were significantly reduced and nephron number was reduced by 24%. There was no difference in renin, angiotensinogen, or AT(1) and AT(2) receptor mRNA expression levels in the IUGR kidneys compared with controls. We conclude that fetal growth restriction late in nephrogenesis can lead to a marked reduction in nephron endowment but does not affect renal corpuscle or macula densa size, or renal RAS gene expression.

Topics: Angiotensin II; Angiotensinogen; Animals; Body Weight; Erythrocyte Indices; Female; Fetal Growth Retardation; Fetal Weight; Fetus; Gene Expression; Gestational Age; Kidney; Nephrons; Organ Size; Pregnancy; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sheep

To investigate whether catch-up growth after maternal malnutrition would favor the development of obesity in adulthood.. Pregnant rats were submitted to protein or calorie restriction during the course of gestation. During lactation, pups were protein-restricted, normally fed, or overfed [reduced litter size, control (C) diet]. At weaning, rats were transferred to chow or to a hypercaloric diet (HCD) known to induce obesity. Body weight, food intake, blood parameters, glucose tolerance, adipocyte cellularity, and adipose factors contributing to cardiovascular disease development were measured.. Protein and calorie restriction during gestation led to growth retardation at birth. If malnutrition was prolonged throughout lactation, adult body weight was permanently reduced. However, growth-retarded offspring overfed during the suckling period underwent a rapid catch-up growth and became heavier than the normally fed Cs. Offspring of calorie-restricted rats gained more weight than those of dams fed protein-restricted diet. Feeding an HCD postnatally amplified the effect of calorie restriction, and offspring that underwent catch-up growth became more obese than Cs. The HCD was associated with hyperphagia, hyperglycemia, hyperinsulinemia, glucose intolerance, insulin resistance, and adipocyte hypertrophy. The magnitude of effects varied depending on the type and the timing of early malnutrition. The expression of genes encoding factors implicated in cardiovascular disease was also modulated differently by early malnutrition and adult obesity.. Catch-up growth immediately after early malnutrition should be a key point for the programming of obesity.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Angiotensinogen; Animals; Animals, Newborn; Body Weight; Diet; Eating; Female; Leptin; Litter Size; Male; Obesity; Plasminogen Activator Inhibitor 1; Pregnancy; Prenatal Exposure Delayed Effects; Protein-Energy Malnutrition; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Triglycerides

During aging increases in body weight, insulin resistance, and elevated systolic pressure contribute to the development of metabolic syndrome. Long-term systemic blockade of the renin-angiotensin system (RAS) with either an angiotensin (Ang) II type 1 (AT1) receptor antagonist or angiotensin converting enzyme inhibitor improves insulin sensitivity and decreases risk of new onset (type II) diabetes. However, the role of the brain RAS in mediating development of insulin insensitivity during aging is not known. Therefore, we compared responses to an oral glucose load in transgenic rats with selective antisense suppression of brain angiotensinogen (ASrAogen); (mRen2)27 rats with high brain angiotensin II; and control Hannover Sprague-Dawley (SD) rats, at wk 16 and 68 of age. ASrAogen animals had lower body weight than either SD or (mRen2)27 rats at both ages (p < 0.001). The oral glucose tolerance test at 16 wk in (mRen2)27 animals revealed a higher glucose-insulin index (154,421 +/- 11,231 units; p < 0.05) and a lower glucose-insulin index in ASrAogen rats (41,580 +/- 10,923 units, p < 0.05) compared to SD rats (97,134 +/- 19,822 units), suggesting insulin resistance in the (mRen2)27 and enhanced insulin sensitivity in the ASrAogen relative to SD rats. At 68 wk, the glucose-insulin index remained low in the ASrAogen rats as evidence of maintained insulin sensitivity during aging compared with either SD or (mRen2)27 (p < 0.05). SD animals do not differ from (mRen2)27 rats at 68 wk indicating the development of a state of relative insulin resistance with increased age in the SD rats. Moreover, there was a positive correlation (r = 0.44; p < 0.05) between body weight and the glucose-insulin index in SD, but not ASrAogen or (mRen2)27 rats. The relationships between insulin and leptin, insulin and glucose, and leptin and body weight observed in SD rats were absent in ASrAogen and (mRen2)27 rats. We conclude that the glial RAS plays a role in development of insulin resistance as well as influencing weight gain associated with early aging.

Topics: Aging; Angiotensinogen; Animals; Blood Glucose; Body Weight; Brain Chemistry; Insulin; Insulin Resistance; Leptin; Male; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley

Recent evidence suggests that the intrarenal renin-angiotensin system (RAS) may play an important role in the development of glomerular changes associated with diabetic nephropathy. In this study, the glomerular RAS was examined in male Sprague-Dawley rats made diabetic with streptozotocin (STZ), and the findings compared with those obtained in control nondiabetic rats. In diabetic rat glomerular extracts, angiotensinogen and angiotensin II (ANG II) levels were increased significantly by 2.2- and 1.9-fold, respectively, compared with nondiabetic controls. No significant differences in ANG I and angiotensin-converting enzyme (ACE) levels were observed between these groups. The HPLC analysis of the glomerular extracts demonstrated that exogenous ANG I was converted into various ANG peptides including ANG II, ANG1-9, and ANG1-7. A significant increase in formation of ANG II from exogenous ANG I was observed in STZ rats compared with control rats. Preincubation of glomerular extracts with captopril resulted in a 20-30% decrease in ANG II conversion from exogenous ANG I in diabetic and control rats. The possible role of ANG1-9 in formation of ANG II was examined by HPLC. Exogenous ANG1-9 in glomerular extracts was converted into ANG II, this conversion being significantly higher in STZ rats than in control rats. These findings provide new information that ANG1-9 is produced in rat glomerular extracts, can be converted to ANG II, and that this conversion is also stimulated in diabetic rat glomeruli. Thus this study demonstrates that in diabetic rats, glomerular ANG II levels are increased due to an increase in angiotensinogen and an increase in the formation of ANG II.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Glucose; Body Weight; Captopril; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Kidney Glomerulus; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley

To test the hypothesis that changes in gene expression that may accompany angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) gene polymorphism cause alteration in angiotensin and bradykinin peptide levels.. Mice with one or two genes for AGT and ACE allow assessment of the effects of modest alteration in AGT and ACE gene expression on angiotensin and bradykinin peptide levels.. Angiotensin and bradykinin peptides were measured in the blood, kidney, heart, lung, adrenal, brain, and aorta of mice that were either wild-type (+/+), heterozygous (+/-) or null (-/-) for either the AGT or ACE gene.. Angiotensin I and angiotensin II were not detectable in blood or tissues of AGT -/- mice, which had increased bradykinin levels in kidney and lung. ACE -/- mice had markedly reduced angiotensin II levels and increased bradykinin levels in blood and tissues. However, despite reduced AGT and ACE gene expression, angiotensin and bradykinin peptide levels in AGT and ACE +/- mice were no different from the levels in wild-type mice.. Although the AGT and ACE genes are fundamental determinants of angiotensin and bradykinin peptide levels, compensatory mechanisms attenuate the effect of modest change in AGT and ACE gene expression on the levels of these peptides. Identification of these compensatory mechanisms may provide new candidate genes for investigation in humans.

Topics: Angiotensinogen; Angiotensins; Animals; Blood Pressure; Body Weight; Bradykinin; Female; Gene Dosage; Genotype; Male; Mice; Mice, Inbred C57BL; Peptidyl-Dipeptidase A

Transgenic rats with targeted decreased glial expression of angiotensinogen (ASrAogen rats) did not show an increase in systolic pressure compared with Sprague-Dawley (SD) rats during aging (15-69 wk of age). ASrAogen animals had lower body weights throughout the study, similar to reports for animals with systemic knockout of angiotensinogen or treated long term with renin-angiotensin system (RAS) blockers. Further characterization of indexes of growth and metabolism in ASrAogen rats compared with (mRen2)27 and SD rats, which express elevated versus normal brain and tissue angiotensin II levels, respectively, revealed that serum leptin was 100-200% higher in SD and (mRen2)27 rats at 46 wk and 69 wk of age. Consistent with low serum leptin, ASrAogen rats had higher food intake (73%) compared with SD or (mRen2)27 rats. (mRen2)27 rats had higher resting insulin levels than ASrAogen rats at all ages. Insulin levels were constant during aging in ASrAogen rats, whereas an increase occurred in SD rats, leading to higher insulin levels at 46 and 69 wk of age compared with ASrAogen rats. IGF-1 was comparable among strains at all ages, but (mRen2)27 rats had longer and ASrAogen rats had shorter tail lengths versus SD rats at 15 wk of age. In conclusion, reduced expression of glial angiotensinogen blunts the age-dependent rise in insulin levels and weight gain, findings that mimic the effects of long-term systemic blockade of the RAS or systemic knockout of angiotensinogen. These data implicate glial angiotensinogen in the regulation of body metabolism as well as hormonal mechanisms regulating blood pressure.

Topics: Aging; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Body Weight; Brain; Heart Rate; Insulin; Leptin; Neuroglia; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Tail

The aim of this study was to clarify the role of the renal renin-angiotensin system (RAS) in diabetic nephropathy (DN), which was induced by injection of streptozotocin (STZ). Male CBA/N and CBA/J mice were compared in this study. The former possesses a single renin gene, Ren1, whereas the latter carries two renin genes, Ren1 and Ren2. To examine the molecular dynamics of renal RAS, including renin, angiotensinogen (Agt), angiotensin-converting enzyme (Ace), angiotensin type 1 (Agtr1) and type 2 (Agtr2) receptors in experimental DN, we performed laser-microdissection (LMD) followed by reverse transcriptase nested polymerase chain reaction using each specific primer pairs and immunohistochemistry for renin and angiotensin II. CBA/N mice had a higher response after injection of STZ than CBA/J mice, showing a significant increase of the kidney/body weight ratio, although there was no significant difference between the two strains for the blood glucose level or pancreatic beta-cell response. The onset of renal pathological changes associated with DN was earlier and more severe in CBA/N mice than in CBA/J mice. Distinct immunoreactivities for renin and angiotensin II were newly distributed on the flattened epithelial cells in the dilated distal tubules in the cortex as well as the collecting ducts in the cortex and medulla, and were demonstrated more intensely in CBA/N mice than in CBA/J mice. Microdissectional analysis in both DN models revealed a higher incidence of RAS-related gene expression in CBA/J, Ren 1 Ren 2 mice than in CBA/N, Ren 1 mice. These findings suggest that intrarenal RAS plays an important role in the onset of renal pathological changes associated with DN. Additionally, Ren 1 mice have more severe histopathological nephropathy than Ren1 Ren2 mice, followed by marked production of angiotensin II.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Immunohistochemistry; Insulin; Kidney; Male; Mice; Mice, Inbred CBA; Mice, Inbred DBA; Mice, Inbred MRL lpr; Organ Size; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Specific Pathogen-Free Organisms; Up-Regulation

Adipose tissue represents an important source of angiotensinogen (AGT). We investigated the effect of obesity induced by a high-fat diet on the expression of mouse (mAGT) and human AGT (hAGT) genes in liver, kidney, and heart and different adipose depots in normal mice (C57BL/6J), and in transgenic mice expressing the hAGT gene under the control of its own promoter. Mice were fed a high-fat diet (45% kcal) or normal chow (10% kcal) for 10 and 20 wk. The expression of mAGT and hAGT mRNA was quantified using an RNAse protection assay. Mice on the high-fat diet exhibited increased weight, fat mass, and plasma leptin. Expression of mAGT or hAGT genes was not affected by high-fat diet in nonadipose tissues, brown adipose tissue, or subcutaneous white fat. In contrast, high-fat diet increased both mAGT and hAGT gene expression in visceral adipose depots (omental, reproductive, and perirenal fat). Thus obesity-induced by a high-fat diet is associated with a tissue-specific increased expression of both mouse and human AGT genes in intra-abdominal adipose tissue. Our findings also suggest that 1.2 kb of regulatory sequences present in the hAGT transgene are sufficient to transcriptionally respond to a high-fat diet in an adipose-specific and depot-specific manner.

Topics: Adipose Tissue; Angiotensinogen; Animals; Body Weight; Dietary Fats; Gene Expression; Hypertension; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; RNA, Messenger

Evidence on the effect of salt intake on the interaction between angiotensinogen (AGT) T174M polymorphism and high blood pressure is sparse. We therefore conducted a large population-based cross-sectional study of 2,823 men and women aged 30-74 in a Japanese farming community to examine associations between AGT polymorphism and blood pressure levels stratified by age (30-64 and 65-74), body mass index (BMI; median), and salt intake (median) estimated by 24-h urine collection and dietary questionnaire. Our a priori hypothesis is that individuals, particularly younger and non-overweight individuals, with the 174M allele have elevated blood pressure levels in response to higher sodium intake, and thus the association between T174M polymorphism and blood pressure is more evident among individuals with higher sodium intake than those with lower sodium intake. There were no differences in systolic or diastolic blood pressure levels (SBP or DBP) between the TT and TM+MM genotype groups overall. However, the mean difference in DBP between the TM+MM and TT groups was +1.0 mmHg in subjects of younger age (p=0.06), +1.7 mmHg in non-overweight subjects (BMI<23.5 kg/m2, p=0.01), and +2.3 mmHg in younger and non-overweight subjects (p = 0.002). Furthermore, among younger and non-overweight subjects, blood pressure differences were larger for those with higher urinary sodium excretion (+3.1 mmHg, p = 0.03), those with a higher sodium/potassium excretion ratio (+4.1 mmHg, p=0.007), those with higher present sodium intake score (+3.0 mmHg, p=0.003), and those with higher past sodium intake score (+3.4 mmHg, p<0.001). In conclusion, AGT T174M polymorphism was associated with higher DBP levels in younger and non-overweight Japanese. This association was more evident among subjects with higher sodium intake.

Topics: Adult; Aged; Angiotensinogen; Blood Pressure; Body Weight; Female; Genotype; Humans; Hypertension; Japan; Male; Middle Aged; Polymorphism, Genetic; Rural Population; Sodium, Dietary

The renin-angiotensin system is involved in adipocyte growth and differentiation and possibly in adipose tissue metabolism.. To investigate the association of polymorphism in the angiotensin-converting enzyme (ACE) I/D gene, angiotensinogen M235T gene, and angiotensin II type 1 receptor A1166C gene with body mass index, body fat pattern, and obesity-associated hypertension.. Cross-sectional longitudinal study.. The Olivetti factories in Marcianise and Pozzuoli, suburbs of Naples, Italy.. 959 adult men, 25 to 75 years of age.. Renin-angiotensin system polymorphism, anthropometric indexes, blood pressure, and serum glucose and insulin levels.. No association was detected between angiotensinogen or angiotensin II type 1 receptor gene polymorphism and anthropometric indexes or blood pressure. For ACE I/D polymorphism, significant age-genotype interaction was detected on cross-sectional observation; the relation of body mass index, waist circumference, and diastolic blood pressure to age was significantly greater in persons with the DD genotype than in those with the ID or II genotype. Overweight and abdominal adiposity were more common in men with the DD genotype, particularly among older participants (51.1% vs. 36.5% and 33.1% vs. 22.0%, respectively). Odds ratios were 1.82 (95% CI, 1.16 to 2.87) for overweight and 1.76 (CI, 1.06 to 2.90) for abdominal adiposity. Among 314 untreated men first examined 20 years earlier, those with the DD genotype had greater age-adjusted weight gain (1.45 kg [CI, 0.12 to 2.78 kg]) and change in diastolic blood pressure (2.83 mm Hg [CI, 0.39 to 5.28 mm Hg]). The relative risk for overweight was 2.34 (CI, 1.32 to 4.15) among participants with the DD genotype versus those with the ID or II genotype.. The ACE I/D polymorphism was a significant predictor of overweight and abdominal adiposity in men. DD homozygosity was associated with larger increases in body weight and blood pressure in aging persons, as well as with higher incidence of overweight.

Topics: Abdomen; Adipose Tissue; Adult; Aged; Angiotensinogen; Anthropometry; Body Weight; Cross-Sectional Studies; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Obesity; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System

Topics: Abdomen; Adipose Tissue; Adult; Aged; Angiotensinogen; Anthropometry; Body Weight; Humans; Hypertension; Male; Middle Aged; Obesity; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System

The aim of the present study was to assess our hypothesis that the renin-angiotensin system (RAS) is responsible for cold-induced hypertension and cardiac hypertrophy. Two groups of wild-type (WT) mice and 2 groups of angiotensinogen gene knockout (Agt-KO) mice (6 per group) were used. After blood pressures (BP) of the four groups were measured 3 times at room temperature (25 degrees C), 1 WT and 1 Agt-KO group were exposed to cold (5 degrees C). The remaining groups were kept at 25 degrees C. BP of the cold-exposed WT group increased significantly in 1 week of cold exposure and rose gradually to 168+/-7 mm Hg by week 5, whereas the BP of the Agt-KO group did not increase until week 3. The cold-induced increase in BP (DeltaBP) was decreased significantly in the Agt-KO mice (19+/-3 mm Hg) compared with that of the WT mice (61+/-5 mm Hg) by 5 weeks of exposure to cold. Both WT and Agt-KO groups had cardiac hypertrophy in cold to the same extent. Agt-KO caused a significant increase in nitric oxide (NO) production. Thus, the RAS may inhibit NO formation. Chronic cold exposure decreased NO production, which may be mediated partially by activation of the RAS. These results strongly support that the RAS plays a critical role in the development of cold-induced hypertension but not cardiac hypertrophy. Moreover, the role of the RAS in cold-induced hypertension may be mediated in part by its inhibition on NO production. The findings also reveal the possible relation between the RAS and NO in cardiovascular regulation.

Topics: Angiotensinogen; Animals; Blood Pressure; Body Weight; Brain; Cold Temperature; Female; Gene Expression; Genotype; Hypertension; Hypothalamus; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Nitrates; Nitrites; Norepinephrine; Organ Size; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The functional significance of cross-regulation between the renin-angiotensin system (RAS) and tumor necrosis factor (TNF) has been established in nonmyocyte cell types; however, the degree and functional significance of the interaction between RAS and TNF has not been characterized in the heart.. We examined the expression of components of the RAS in a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF. When examined at 4, 8, and 12 weeks of age, the MHCsTNF mice had increased activation of myocardial RAS, as shown by an increase in ACE mRNA level and ACE activity and increased angiotensin II peptide levels. Furthermore, myocardial angiotensin receptor mRNA and protein levels were reduced in the MHCsTNF mice, consistent with homologous desensitization of the receptors. However, expression of renin and angiotensinogen was not increased in MHCsTNF mice compared with littermate controls. To determine the functional significance of RAS activation in the MHCsTNF mice, we treated the mice with an angiotensin type I receptor antagonist, losartan (30 mg/kg), or diluent from 4 to 8 weeks of age. Analysis of cardiac structure with MRI showed that treatment with losartan normalized left ventricular mass and wall thickness. Furthermore, treatment with losartan reduced myocardial collagen content and reduced the incidence of myocyte apoptosis.. Taken together, these results show that there are functionally significant interactions between RAS and TNF in the heart and that these interactions play an important role in the development and progression of left ventricular remodeling.

Topics: Age Factors; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Body Weight; Cardiomegaly; Collagen; Hemodynamics; Losartan; Mice; Mice, Transgenic; Myocardium; Organ Size; Organ Specificity; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; RNA, Messenger; Tumor Necrosis Factor-alpha; Ventricular Remodeling

The present study evaluated the importance of ovarian functions and the renin-angiotensin system in the progression of the right ventricular (RV) hypertrophy. Female Sprague-Dawley rats were bilaterally ovariectomized (Ovx) and injected with monocrotaline (MCT, 60 mg/kg, sc). Four weeks after MCT-treatment, only the male and Ovx female rats showed marked RV hypertrophy. The hypertrophied RV of the male-MCT and Ovx-MCT rats exhibited remarkably elevated renin mRNA levels. Gene expression levels of angiotensinogen, TGF-beta1, and endothelin-1 in the hypertrophied RV also increased, but to the less degree than did the renin mRNA. To investigate beneficial effects of estrogen or enalapril on progression of the pulmonary hypertension and RV hypertrophy, histological changes of the lung and heart were examined. Sham-MCT female rats showed histological changes indicating pulmonary hypertension without RV hypertrophy. In contrast, Ovx-MCT rats showed marked RV hypertrophy with pathological changes, denoting severe pulmonary and myocardial injuries. Estrogen-or enalapril-treated Ovx-MCT rats did not show RV hypertrophy, and showed remarkably ameliorated ultrastructural changes in the lung and RV. These results from this rat model suggest that both estrogen and inhibition of the renin-angiotensin system have protective functions against the development of the pulmonary hypertension and cardiac remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Body Weight; Densitometry; Disease Progression; Enalapril; Endothelin-1; Estrogens; Female; Hypertrophy, Right Ventricular; Male; Microscopy, Electron; Monocrotaline; Ovariectomy; Rats; Rats, Sprague-Dawley; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sex Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

The objective of the study was to analyze the relationship of polymorphisms of the angiotensinogen gene with changes in body weight during 3 y of antihypertensive treatment, in a group of young adults with essential hypertension.. Essential hypertensives, less than 50 y old, never previously treated with antihypertensive drugs and in the absence of diabetes mellitus were included. After the initial evaluation, patients were treated using only non-pharmacological measures (n=29), beta-blockers (n=40) or angiotensin-converting enzyme inhibitors (n=66). Resting blood pressure, biochemical profile and body weight at the beginning and yearly were measured. The polymorphism A-6G of the angiotensinogen gene located in the promoter region was analyzed.. One-hundred and thirty-five patients were included. Genotypes of the A-6G polymorphism of the AGT gene were in Hardy-Weinberg equilibrium (AA 34, AG 63, GG 38). No significant differences were observed among genotypes in terms of age, body mass index, body weight, systolic or diastolic blood pressure. No significant differences in the genotype distribution or in the allele frequencies were observed, although the A allele was most frequent among the obese subjects. During the 3 y of antihypertensive treatment, there was a trend to increase weight despite the dietary recommendations. The slopes of body weight over time, adjusted by age and baseline BMI, differed significantly among the homozygote genotypes (P=0.006). The highest were for those with the AA genotype and the lowest for the GG genotype (1.180+/-0.25 and -0.128+/-0.24 kg/y; P=0.0001). The influence of the genotype in the changes on body weight remained significant after considering its interaction with the kind of antihypertensive treatment, although among subjects carrying the AA genotype those treated with ACEi showed the least body weight change. Furthermore, A-6G genotypes had the largest influence on weight changes, accounting for 19% of the variance, when age, sex and initial body mass index were included in the model.. In a group of young adult hypertensive subjects, there was a trend to increase weight despite dietary recommendations. Subjects with the AA genotype were those with the largest weight gain, but this effect was modified by the antihypertensive treatment.

Topics: Adrenergic beta-Antagonists; Adult; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Antihypertensive Agents; Body Mass Index; Body Weight; Female; Follow-Up Studies; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Time Factors

Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts. Angiotensin II (Ang II) type 1A (AT1A), an Ang II receptor, regulates cardiovascular homeostasis oppositely. Disruption of GC-A induces cardiac hypertrophy and fibrosis, suggesting that GC-A protects the heart from abnormal remodeling. We investigated whether GC-A interacts with AT1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT1A in mice.. We generated double-knockout (KO) mice for GC-A and AT1A by crossing GC-A-KO mice and AT1A-KO mice and blocked AT1 with a selective antagonist, CS-866. The cardiac hypertrophy and fibrosis of GC-A-KO mice were greatly improved by deletion or pharmacological blockade of AT1A. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, transforming growth factors beta1 and beta3, were also strongly inhibited. Furthermore, stimulation of AT1A by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals.. These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT1A signaling and that GC-A inhibits AT1A signaling-mediated excessive remodeling.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Fibrosis; Gene Targeting; Guanylate Cyclase; Heart Rate; Heart Ventricles; Hypertension; Imidazoles; Mice; Mice, Knockout; Myocardium; Natriuretic Peptide, Brain; Olmesartan Medoxomil; Organ Size; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Ventricular Remodeling

Physiological changes occurring in the mother during pregnancy can determine the outcome of pregnancy in terms of birthweight and neonatal viability. Maternal adaptations include plasma volume expansion linked to enhanced activity of the renin-angiotensin system (RAS). The present study was designed to determine whether these changes occur very early in gestation, and the extent to which maternal nutrient restriction may compromise the maternal RAS. Using sheep, we have investigated the effects of pregnancy per se, maternal nutrient restriction and later restoration of maternal diet on maternal body weight, plasma volume and plasma renin concentration (PRC), and angiotensinogen (Aogen) and arginine vasopressin (AVP) concentration. During the period of placental growth (i.e. 28-80 days gestation) ewes were fed either a nutrient-restricted (NR) diet or were well fed (WF). NR ewes consumed between 3.2 and 3.8 MJ day(-1) of metabolisable energy (ME) which is close to 60 % of requirements taking into account the ME required for both ewe maintenance and growth of the conceptus in order to produce a 4.5 kg lamb at term. WF ewes consumed 150 % of ME requirements. Restoration of maternal diet between 80 and 140 days gestation (i.e. fed to satiety and consuming between 8 and 10.9 MJ day(-1), which is close to 150 % of ME requirements) followed previous nutrient restriction. Between pre-conception and 28 days gestation, plasma volume increased in conjunction with a decline in PRC and Aogen concentration. During the period of nutrient restriction ewe body weight did not increase and plasma volume was lower in NR than WF ewes. During this time there was no effect of maternal nutrition on PRC; however, Aogen concentration was lower in the NR group. From 80 days gestation following the rise in food intake for previously NR ewes, greater increases in ewe body weight, plasma volume and PRC occurred up to term compared with ewes that were well fed throughout gestation. Plasma AVP concentration was not significantly affected by either maternal nutrition or gestational age. In conclusion, the stimulus of moderately severe maternal nutrient restriction evoked smaller rises in maternal weight, plasma volume and Aogen concentration than occurred in ewes that were well fed throughout gestation. Following the restoration of maternal diet after 80 days gestation, PRC gradually rose to peak at term. These adaptations in the maternal RAS during the critical period of placental growt

Topics: Angiotensinogen; Animals; Arginine Vasopressin; Body Weight; Erythrocyte Count; Female; Food Deprivation; Nutritional Physiological Phenomena; Plasma Volume; Pregnancy; Pregnancy, Animal; Renin; Renin-Angiotensin System; Sheep

Elevated plasma angiotensinogen (AGT) levels have been demonstrated in insulin-resistant states such as obesity and type 2 diabetes mellitus (DM2), conditions that are directly correlated to hypertension. We examined whether hyperinsulinemia or hyperglycemia may modulate fat and liver AGT gene expression and whether obesity and insulin resistance are associated with abnormal AGT regulation. In addition, because the hexosamine biosynthetic pathway is considered to function as a biochemical sensor of intracellular nutrient availability, we hypothesized that activation of this pathway would acutely mediate in vivo the induction of AGT gene expression in fat and liver. We studied chronically catheterized lean (approximately 300 g) and obese (approximately 450 g) Sprague-Dawley rats in four clamp studies (n = 3/group), creating physiological hyperinsulinemia (approximately 60 microU/ml, by an insulin clamp), hyperglycemia (approximately 18 mM, by a pancreatic clamp using somatostatin to prevent endogenous insulin secretion), or euglycemia with glucosamine infusion (GlcN; 30 micromol. kg(-1). min(-1)) and equivalent saline infusions (as a control). Although insulin infusion suppressed AGT gene expression in fat and liver of lean rats, the obese rats demonstrated resistance to this effect of insulin. In contrast, hyperglycemia at basal insulin levels activated AGT gene expression in fat and liver by approximately threefold in both lean and obese rats (P < 0.001). Finally, GlcN infusion simulated the effects of hyperglycemia on fat and liver AGT gene expression (2-fold increase, P < 0.001). Our results support the hypothesis that physiological nutrient "pulses" may acutely induce AGT gene expression in both adipose tissue and liver through the activation of the hexosamine biosynthetic pathway. Resistance to the suppressive effect of insulin on AGT expression in obese rats may potentiate the effect of nutrients on AGT gene expression. We propose that increased AGT gene expression and possibly its production may provide another link between obesity/insulin resistance and hypertension.

Topics: Adipose Tissue; Angiotensinogen; Animals; Blood Glucose; Body Composition; Body Weight; Gene Expression Regulation; Glucosamine; Glucose Clamp Technique; Hexosamines; Hyperglycemia; Hyperinsulinism; Infusions, Intravenous; Insulin; Insulin Resistance; Liver; Male; Obesity; Rats; Rats, Sprague-Dawley

We postulated that chronic placental insufficiency would be associated with reduced expression of renal renin and angiotensinogen genes in the fetal sheep. Placental development was restricted in ewes by removing the majority of caruncles prior to mating (placentally restricted (PR) group). The weights of PR fetuses were significantly reduced (P < 0.05, 2.98 +/- 0.33 kg) compared to control fetuses (4.20 +/- 0.30 kg). Kidney weights were also significantly reduced in the PR fetuses (P < 0.05, 8.4 +/- 0.9 g) compared with control fetuses (12.2 +/- 1.3 g). The ratios of renal renin/-actin mRNA levels were significantly reduced in PR fetuses (P < 0.001, 0.35 +/- 0.02) when compared to control animals (0.98 +/- 0.13). The renal angiotensinogen mRNA/18S rRNA ratio was significantly lower (P < 0.05, 0.28 +/- 0.13) in PR fetuses compared with control fetuses (0.72 +/- 0.10), while hepatic angiotensinogen was unaffected. There was a positive correlation between renal renin mRNA and renal angiotensinogen mRNA levels (r = 0.65, P < 0.05, n = 12). It is unlikely that these changes in renal angiotensinogen and renin mRNA were due to the small increment in plasma cortisol levels (< 5 nmol l-1). There was, however, a positive correlation between arterial PO2 and renal renin mRNA (r2 = 0.77, P < 0.01). Plasma renin levels were not different between the two groups. Thus, restriction of nutrient and oxygen supply throughout fetal life was associated with suppression of renal renin and renal angiotensinogen gene expression, with no effect on hepatic angiotensinogen mRNA levels. This specific suppression of fetal renal renin and angiotensinogen expression could alter the activity of the intrarenal RAS and so affect growth and development of the kidney.

Topics: Angiotensinogen; Animals; Autoradiography; Body Weight; Female; Fetus; Hydrocortisone; Liver; Organ Size; Oxygen Consumption; Placental Insufficiency; Pregnancy; Renin; Renin-Angiotensin System; Ribonucleases; RNA, Messenger; Sheep

Left ventricular hypertrophy (LVH) entails numerous functional and molecular changes that ultimately lead to cardiac insufficiency. The renin-angiotensin system and adrenergic receptor signalling pathway have both been implicated in LVH progression and interactions between these factors may precipitate contractile dysfunction. We therefore investigated cardiac function in hypertensive rats transgenic for the human renin and angiotensinogen genes (TGR) having a genetic activation of the renin-angiotensin system, stroke-prone spontaneously hypertensive rats (SHR) and normotensive controls (CTR) aged 6 weeks. The isolated perfused heart model was used and the effect of isoproterenol (0.1-1000 nmol/L on cardiac function was studied. Cardiac protein and gene expression was studied by Western blot and RNase protection assay. TGR had 75 mmHg higher blood pressure and a 24% higher cardiac/body weight ratio than CTR; blood pressure in SHR was 17 mmHg higher without heart weight difference (p < 0.05). Basal Pmax, +dP/dt and -dP/dt were higher in TGR and SHR compared with CTR hearts. Isoproterenol stimulated these parameters by a maximum factor 6-8 in CTR and SHR but had almost no effect in TGR (p < 0.05). Basal CF per g heart weight was similar in all experimental groups. Isoproterenol produced a significantly smaller vasodilation in TGR compared with CTR or SHR. beta 1 and beta 2 receptor and Gs alpha proteins were similar in TGR, SHR and CTR. Gi alpha was increased in TGR hearts (p < 0.05). Converting enzyme and atrial natriuretic factor mRNA expression was increased (p < 0.01) while beta 1 receptor, adenylyl-cyclase V, SERCA2a and phospholamban mRNA expression was unchanged in TGR compared with CTR. Thus, LVH in TGR is characterised by early adrenergic dysfunction and beta 1 receptor signalling abnormalities indicating progressive functional deterioration. The data may serve as support for an early preventive intervention in angiotensin-II dependent cardiac hypertrophy and may have also implications for patients with genetic alterations of the renin-angiotensin system.

Topics: Adrenergic beta-Agonists; Angiotensinogen; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Blood Pressure; Blotting, Western; Body Weight; Cardiotonic Agents; Gene Expression Regulation; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Heart; Humans; Hypertension; Hypertrophy, Left Ventricular; Isoproterenol; Male; Myocardial Contraction; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Renin; Renin-Angiotensin System; Serine Proteinase Inhibitors; Vasodilator Agents

To examine the interaction of sodium intake with genetic variations of the angiotensinogen gene and hypertension.. A community-based case-reference study.. Two rural Japanese communities.. Non-overweight and non-drinking Japanese men and women: 229 hypertensives and 229 age-, sex- and community-matched normotensives aged 32 to 83 years.. Polymorphisms of the angiotensinogen gene detected by an allele-specific polymerase chain reaction. A priori hypothesis is individuals with 174M (threonine-to-methionine substitution) or 235T (methionine-to-threonine substitution) allelic variations may have an elevated risk of hypertension when they have a high sodium intake, estimated by 24-h urine collection and a dietary questionnaire.. The genotypic frequency of the haplotype including both the 174M and 235T alleles was higher among hypertensives than among normotensives (23 versus 14%, P= 0.02). The frequency of the 174M allele was specifically higher among hypertensives than normotensives (12 versus 7%, P=0.01), and the odds ratio of hypertension associated with the 174M (versus 174T) allele was 1.8 [95% confidence interval (CI) 1.1-3.0, P=0.01]. The frequency of the 235T allele did not vary between the two groups (80 versus 82%, P= 0.40). The relationship between the 174M allele and hypertension was more evident among persons who had higher urinary sodium excretion (> = 166 mmol/day) than those with lower excretion (< 166 mmol/day): odds ratio 2.5 (95% CI, 1.2-5.2), P=0.01 versus 1.5 (95% CI, 0.7-3.1), P= 0.31; P for interaction = 0.04, and this trend was primarily observed for early-onset hypertension (< 55 years at onset). A similar but nonsignificant association was observed when stratified using present and past sodium intake scores derived from questionnaires.. Angiotensinogen genotype may affect the development of early-onset hypertension among Japanese, particularly in those who have a high sodium intake.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; Alcohol Drinking; Angiotensinogen; Asian People; Blood Pressure; Body Weight; Case-Control Studies; DNA Primers; Female; Gene Frequency; Haplotypes; Humans; Hypertension; Japan; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Renin-Angiotensin System; Rural Population; Sodium, Dietary

A novel approach was employed to assess the contribution of the renin-angiotensin system (RAS) to obstructive nephropathy in neonatal mice having zero to four functional copies of the angiotensinogen gene (Agt). Two-day-old mice underwent unilateral ureteral obstruction (UUO) or sham operation; 28 days later, renal interstitial fibrosis and tubular atrophy were quantitated. In all Agt genotypes, UUO reduced ipsilateral renal mass and increased that of the opposite kidney. Renal interstitial collagen increased after UUO linearly with Agt expression, from a fractional area of 25% in zero-copy mice to 54% in two-copy mice. Renal expression of transforming growth factor-beta1 was increased by ipsilateral UUO in mice expressing Agt, but not in zero-copy mice. However, the prevalence of atrophic tubules due to UUO did not vary with Agt expression. Blood pressure was not different in all groups, except for a reduction in sham zero-copy mice. We conclude that a functional RAS is not necessary for compensatory renal growth. This study demonstrates conclusively that angiotensin regulates at least 50% of the renal interstitial fibrotic response in obstructive nephropathy, an effect independent of systemic hemodynamic changes. Angiotensin-induced fibrosis likely is a mechanism common to the progression of many forms of renal disease.

Topics: Angiotensinogen; Animals; Blood Pressure; Body Weight; Collagen; Gene Dosage; Gene Targeting; Kidney Diseases; Kidney Tubules; Mice; Mice, Inbred Strains; Organ Size; Renin-Angiotensin System; RNA, Messenger; Transforming Growth Factor beta; Ureteral Obstruction

Plasma and left ventricular (LV) renin and angiotensinogen concentrations were assessed in a rat model of pressure-overload cardiac hypertrophy to determine if myocardial levels remained proportional to plasma levels over time. Three days after subdiaphragmatic aortic constriction (AC), LV hypertrophy was evident and renin concentrations in both plasma and LV, although not significantly elevated, were positively correlated with relative cardiac mass. After 42 days AC, LV hypertrophy remained, plasma and LV renin and angiotensinogen levels were not different from shams, and there was no correlation between renin and relative cardiac mass. Furthermore, LV renin and angiotensinogen concentrations remained at approximately 25 and 4%, respectively, of those in plasma throughout the experiment. Myocytes from 3-day AC and sham-treated rats contained little renin as did LV from 48-h anephric rats. Incubations using calculated concentrations of myocardial interstitial renin and angiotensinogen revealed significant angiotensin I generation. These data suggest that LV renin in this model varies directly with plasma renin, is confined to the interstitial space, and can generate significant intramyocardial angiotensin I.

Topics: Angiotensinogen; Animals; Arterial Occlusive Diseases; Blood Pressure; Body Weight; Cardiomegaly; Female; Heart; Myocardium; Organ Size; Rats; Rats, Sprague-Dawley; Renin; Time Factors

Spontaneous rupture of the internal elastic lamina (IEL) occurs in some arteries of the rat during growth and aging. Inbred, normotensive, Brown Norway (BN) rats are particularly susceptible to rupture of the IEL, especially in the abdominal aorta (AA). Preliminary experiments showed that different angiotensin-converting enzyme (ACE) inhibitors protect against rupture of the IEL in the BN rat to a greater extent than hydralazine, suggesting a role of the renin-angiotensin system (RAS) in this phenomenon. To explore this possibility, we have treated male BN rats from 4.5 to 14 weeks of age with either enalapril or losartan (both at 1, 3, and 10 mg x kg(-1) x d(-1)) or with the calcium antagonists mibefradil (at 3, 10, 30, and 45 mg x kg(-1) x d(-1)) and amlodipine (at 30 mg x kg(-1) x d(-1)). Systolic blood pressure (SBP) was measured weekly, and at the end of treatment we (1) recorded body and heart weights, (2) measured various parameters of the RAS in plasma, (3) quantified interruptions in the IEL on "en face" preparations of AA, and (4) quantified elastin, collagen, and cell proteins in the media of the thoracic aorta. Results showed that enalapril and losartan similarly decrease SBP and rupture of the IEL in the AA, suggesting that enalapril inhibits the latter via a decrease in the production of angiotensin II (Ang II) and not via another effect on ACE. The decrease in IEL rupture and in SBP, as well as the modifications in the parameters of the RAS, were all dose dependent. Mibefradil had little effect on the RAS and, at the highest doses, decreased SBP to an extent similar to that for enalapril at 3 mg x kg(-1) x d(-1) but did not significantly inhibit IEL rupture. Amlodipine decreased SBP, increased plasma renin concentration, and was without effect on IEL rupture. All treatments at the highest doses had a hypotrophic effect on the aortic media but differed in their effects on the heart, with enalapril and losartan decreasing and mibefradil and amlodipine increasing heart weight, suggesting that the inhibition of IEL rupture may be related to a cardiac hypotrophic effect. All these results, taken together, suggest that Ang II plays a role in the rupture of the IEL that is, in part, independent of SBP.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Aorta, Abdominal; Aorta, Thoracic; Aortic Rupture; Benzimidazoles; Blood Pressure; Body Weight; Calcium Channel Blockers; Collagen; Elastic Tissue; Elastin; Enalapril; Heart; Heart Rate; Losartan; Male; Mibefradil; Muscle, Smooth, Vascular; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred BN; Renin; Renin-Angiotensin System; Tetrahydronaphthalenes

The combination of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) inhibition is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on the levels of these peptides. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, 100 mg/kg per day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg per day), to rats by 12 hourly gavage for 7 days. Ecadotril produced diuresis, natriuresis, increased urine cyclic guanosine monophosphate and BK-(1-9) levels, increased Ang II and Ang I levels in plasma, and increased Ang I levels in heart. Perindopril reduced Ang II levels in kidney, and increased BK-(1-9) levels in blood, kidney and aorta. Combined NEP/ACE inhibition produced the summation of these effects of separate NEP and ACE inhibition. In addition, perindopril potentiated the ecadotril-mediated diuresis, natriuresis and decrease in urine BK-(1-7)/BK-(1-9) ratio, which is an index of BK-(1-9) metabolism. Moreover, combined NEP/ACE inhibition increased Ang II levels in plasma and lung. These data indicate that summation of the effects of separate NEP and ACE inhibition provides the basis for the therapeutic efficacy of their combination. Whereas potentiation by perindopril of the diuretic and natriuretic effects of ecadotril may contribute to the therapeutic effects, increased Ang II levels in plasma and lung may compromise the therapeutic effects of combined NEP/ACE inhibition.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Body Weight; Bradykinin; Cyclic GMP; Diuresis; Electrolytes; Heart; Male; Neprilysin; Organ Size; Peptidyl-Dipeptidase A; Protease Inhibitors; Rats; Rats, Sprague-Dawley; Renin

We investigated the relation between atrial natriuretic factor (ANF) gene expression and the status of the renin-angiotensin system (RAS) in aortic tissue in rats made hypertensive by either aortic banding or by deoxycorticosterone acetate (DOCA)-salt administration. These experimental models of hypertension are known to have differences in terms of the status of RAS. ANF messenger RNA (mRNA) levels were measured in aortic tissue by using a newly developed quantitative competitive reverse transcription polymerase chain reaction (QC-RT-PCR) technique. Changes in the proportions of alpha1 and alpha2 isoforms of Na+K+-adenosine triphosphatase (ATPase) mRNA levels were used as indicators of aortic hypertrophy. Treatment with DOCA alone, salt alone, or DOCA-salt for 5 weeks increased aortic-weight/body-weight ratio and aortic angiotensinogen mRNA levels, but did not change alpha1 or alpha2 Na+K+-ATPase mRNA levels. Aortic ANF mRNA levels had a tendency to increase after treatment with DOCA, salt, or DOCA-salt, but this change did not reach statistical significance. Suprarenal aortic banding for 6 weeks or 12 weeks increased aortic-weight/body-weight ratio (12 weeks), decreased alpha2 Na+K+-ATPase and angiotensinogen mRNA levels, but did not affect alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. Treatment with ramipril, an angiotensin-converting enzyme (ACE) inhibitor was carried out for 6 weeks just after aortic banding (prevention experiment) or after 6 weeks in rats that were banded for the previous 6 weeks (regression experiment). High-dose ramipril (1 mg/kg)--a treatment known to inhibit both tissue and circulating RAS--normalized aortic-weight/body-weight ratio, and also normalized alpha2 Na+K+-ATPase mRNA levels. Aortic angiotensinogen mRNA levels of banded rats treated with high-dose ramipril was higher than those of the normal control, sham operated, and banded rats. Treatment with high-dose ramipril did not affect alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. Low-dose ramipril (10 microg/kg)--a treatment that selectively inhibits tissue RAS--normalized aortic-weight/body-weight ratio but did not normalize alpha2 Na+K+-ATPase mRNA levels (regression experiment) or angiotensinogen mRNA levels (prevention experiment) and did not change either alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. The results suggest that, in contrast to previous findings in heart and kidney, the regulation of ANF mRNA levels in aortic tissue is largely independent

Topics: Angiotensinogen; Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Desoxycorticosterone; Gene Expression; Gene Expression Regulation; Hypertension; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium-Potassium-Exchanging ATPase

We measured blood pressure and related clinical phenotypes in 497 adult native Canadians from an isolated community in Northern Ontario. We analyzed their DNA for genotypes of angiotensinogen. We found that the frequency of the T235 variant of the angiotensinogen gene was 0.89 in this sample. This variant was associated with a significantly increased systolic pressure but not diastolic pressure. We also found that sex and body mass were each highly significantly associated with variation in both systolic and diastolic pressures. We found a significant association between age and variation in systolic pressure but not diastolic pressure. We also found a highly significant association between plasma apolipoprotein B concentration and variation in diastolic pressure but not systolic pressure. The high frequency of the angiotensinogen T235 variant suggests that subjects in this young, essentially normotensive population might be predisposed to hypertension, which may become more apparent in the presence of secondary factors.

Topics: Adult; Age Factors; American Indian or Alaska Native; Angiotensinogen; Blood Pressure; Body Weight; Canada; Female; Humans; Hypertension; Male

The aim of the present study was to provide an overview of the role of circulating gonadal steroids on the adaptive changes of the renin-angiotensin system to chronic hypobaric hypoxia (CHH: 4400 m simulated altitude in an hypobaric chamber) and the development of experimental hypertension by bilateral renal ischemia. In order to fulfill this goal, blood pressure (BP), plasma renin activity (PRA) and plasma angiotensinogen concentration (PAoC) as well as haematocrit (Htc) and body weight (BW) of intact and post-puberal castrated normotensive (Nt) and hypertensive (Ht) rats of both sexes were studied following an experimental design similar to that of previous works. Post-puberal castration decreased BP of Nt and Ht rats subjected to CHH. Sexual dimorphism in BP, PRA and PAoC was maintained while that in haematocrit disappeared after castration. Results suggest that circulating sexual steroid hormones are involved in the response of the renin-angiotensin system to the experimental conditions of environmental reduced O2 partial pressure.

Topics: Adaptation, Physiological; Altitude; Angiotensinogen; Animals; Blood Pressure; Body Weight; Female; Gonadal Steroid Hormones; Hematocrit; Hypertension, Renovascular; Hypoxia; Male; Orchiectomy; Ovariectomy; Rats; Rats, Wistar; Renin; Renin-Angiotensin System

Effects of isoproterenol (ISO) on the expression of cardiac angiotensinogen mRNA, angiotensin converting enzyme (ACE) activity, and mechanical functions in spontaneously hypertensive rats were investigated. In the acute phase, defined as within 24 h after the subcutaneous injection of ISO 85 mg/kg, cardiac angiotensinogen mRNA was slightly induced, but ACE activity was not. In the subacute phase, defined as within 8 d after ISO treatment on 2 successive d, both angiotensinogen mRNA expression and ACE activity in the heart were markedly induced. ACE activity in serum was not affected by ISO in either phase. In the subacute phase, ISO reduced body weight and blood pressure, increased ventricular weight and calcium content, and impaired cardiac mechanical function. Oral treatment with imidapril (10 mg/kg/d), an ACE inhibitor, 1 h before each ISO treatment and on the following 6 d, improved ventricular hypertrophy, the elevation of the left ventricular end diastolic pressure, the reduction in contractility, and the prolongation of the time constant. Imidapril significantly suppressed both serum and cardiac ACE activity but did not affect cardiac angiotensinogen mRNA expression in the subacute phase. These results indicate that enhancement of cardiac angiotensinogen mRNA and ACE activity is involved in ISO-induced cardiac dysfunction. Imidapril improved ISO-induced cardiac dysfunction, possibly by suppression of the local ACE activity as well as circulating ACE activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Body Weight; Cardiotonic Agents; Heart Rate; Hypertension; Imidazoles; Imidazolidines; Isoproterenol; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; RNA, Messenger

The influence of altered dietary sodium on angiotensinogen and renin gene expression was examined in young normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Artificial rearing was used to increase or decrease dietary sodium intake during the preweanling period. In normally reared control animals, renal renin and liver angiotensinogen mRNA decreased between 6 and 30 postnatal days of age. In contrast, in the central nervous system, angiotensinogen mRNA increased between 6 and 30 days of age, and renin mRNA remained stable. Dietary sodium manipulation between postnatal days (PD) 6 and 18 significantly influenced renal renin gene expression, with low-sodium diet increasing renin mRNA on PD12 and PD18 and high-sodium diet decreasing renin mRNA on PD18. Liver angiotensinogen mRNA decreased for animals on either diet on PD12 and PD18. Brain angiotensinogen and renin mRNA were not affected by dietary sodium levels. There were no strain-related differences in the response to high and low dietary sodium. These results demonstrate that 1) the peripheral and central renin-angiotensin systems do not have a common ontogenetic pattern of development, 2) they are independently regulated in response to dietary sodium variations, and 3) young WKY and SHR share very similar ontogenetic patterns of angiotensinogen and renin gene expression.

Topics: Angiotensinogen; Animals; Animals, Suckling; Body Weight; Brain; Female; Gene Expression; Hypertension; Kidney; Liver; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Renin; RNA, Messenger; Sodium, Dietary

A variant of the angiotensinogen gene, M235T, has been associated with essential hypertension in selected subjects from Paris, France and Salt Lake City, Utah. In the present report, we studied a population-based sample consisting of 104 subjects diagnosed with hypertension before age 60 and 195 matched normotensive individuals from Rochester, Minnesota. We determined whether there was a relationship between the M235T polymorphism of the angiotensinogen gene and the occurrence of essential hypertension using two methods. First, a contingency chi-square analysis was carried out to test for an association between the M235T polymorphism and hypertension status. Second, multivariable conditional logistic regression was used to determine whether variation at the M235T polymorphism was a significant predictor of the probability of having essential hypertension. We detected no statistically significant association between the M235T polymorphism and the occurrence of essential hypertension. In particular, the association was not significant in either gender or in a subset of severely hypertensive subjects requiring two or more anti-hypertensive medications. Furthermore, variation in the number of M235T alleles did not make a significant contribution to predicting the probability of having essential hypertension, either alone or in conjunction with other predictor variables. These results suggest that the contribution of variation in the angiotensinogen gene to the occurrence of essential hypertension is less than initially suspected, or may not be constant across populations.

Topics: Aged; Alleles; Angiotensinogen; Antiporters; Apolipoprotein C-II; Apolipoproteins C; Blood Pressure; Body Weight; Case-Control Studies; Chi-Square Distribution; Cholesterol; Female; Genetic Variation; Humans; Hypertension; Male; Middle Aged; Minnesota; Polymorphism, Genetic; Regression Analysis; Triglycerides

White adipose tissue is a rich source of angiotensinogen protein and mRNA. Studies in clonal cells suggest that angiotensinogen, and its cleavage product, angiotensin II, are involved in preadipocyte differentiation into mature fat cells. No studies have determined whether angiotensinogen is also involved in adipose tissue development in vivo. In this report, we studied male Wistar rats at two stages of development to determine if angiotensinogen protein and mRNA are increased in retroperitoneal fat depots of rapidly growing young, lean, 8-week-old rats compared to 26-week-old rats that are fatter, but are undergoing less rapid adipose tissue growth. We also assessed renin mRNA and angiotensin I-generating activity, since it is less clear whether renin is locally produced in adipose tissue. We found that angiotensin I-generating activity was measurable in adipose tissue and adipocytes, but renin mRNA was undetectable by northern blot analysis. Angiotensinogen mRNA was abundant in adipocytes, but was absent in stromal-vascular cells of adipose tissue. Angiotensinogen content per 10 million fat cells was approximately threefold higher in 8-week-old rats compared to 26-week-old rats (p < .0002). Angiotensinogen mRNA was approximately twofold higher in adipocytes of 8-week-old rats compared to 26-week-old rats. The age-related decline in angiotensinogen protein and mRNA indicates that the local renin-angiotensin system may play an important role in adipose tissue growth, and possibly contribute to the changes in adipose mass and cellularity seen in old senescent rats.

Topics: Adipocytes; Adipose Tissue; Aging; Angiotensinogen; Animals; Autoradiography; Blotting, Northern; Body Composition; Body Weight; Homeostasis; Male; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; RNA, Messenger

Elevated levels of endogenous angiotensin can cause hypertensive nephrosclerosis as a result of the potent vasopressor action of the peptide. We have produced by gene targeting mice homozygous for a null mutation in the angiotensinogen gene (Atg-1-). Postnatally, Atg-1- animals show a modest delay in glomerular maturation. Although Atg-1- animals are hypotensive by 7 wk of age, they develop, by 3 wk of age, pronounced lesions in the renal cortex, similar to those of hypertensive nephrosclerosis. In addition, the papillae of homozygous mutant kidneys are reduced in size. These lesions are accompanied by local up-regulation of PDGF-B and TGF-beta1 mRNA in the cortex and down-regulation of PDGF-A mRNA in the papilla. The study demonstrates an important requirement for angiotensin in achieving and maintaining the normal morphology of the kidney. The mechanism through which angiotensin maintains the volume homeostasis in mammals includes promotion of the maturational growth of the papilla.

Topics: Aging; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Body Weight; Gene Expression; Growth Substances; Homeostasis; Kidney; Kidney Cortex; Kidney Glomerulus; Kidney Medulla; Mice; Mice, Knockout; Mice, Mutant Strains; Organ Size; Platelet-Derived Growth Factor; Restriction Mapping; RNA, Messenger; Transforming Growth Factor beta

Our previous studies demonstrated that the sexually dimorphic pattern of hypertension in the spontaneously hypertensive rat is androgen dependent. Gonadectomy retards the development of hypertension in young males, but not in females, and administration of testosterone propionate to gonadectomized spontaneously hypertensive rats of both sexes confers a male pattern of blood pressure development. The current study tested the hypothesis that renal and hepatic renin and angiotensinogen gene expression are also androgen dependent in the spontaneously hypertensive rat. Male and female spontaneously hypertensive rats underwent gonadectomy or a sham operation at 4 weeks of age. Subgroups of gonadectomized rats of both sexes were implanted with a 15-mm or 30-mm Silastic capsule filled with testosterone at the same time the gonadectomy was performed; a third group received an empty Silastic capsule. Northern and slot blot analyses were used to characterize and quantitate renin and angiotensinogen messenger RNA (mRNA) in the kidney and liver 18 weeks after the gonadectomy. Blood pressure, plasma renin activity, and hepatic angiotensinogen mRNA levels were higher in intact males than in females. Orchidectomy retarded the development of hypertension and lowered plasma renin and renal and hepatic angiotensinogen mRNA levels, and testosterone replacement restored the male pattern of hypertension and plasma renin and increased renal and hepatic angiotensinogen mRNA. Ovariectomy did not alter blood pressure or plasma renin but did lower renal renin and renal and hepatic angiotensinogen mRNA; testosterone increased blood pressure, plasma renin, renal renin and angiotensinogen mRNA, and hepatic angiotensinogen mRNA levels in ovariectomized females.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensinogen; Animals; Base Sequence; Body Weight; Female; Gene Expression Regulation; Hypertension; Kidney; Liver; Male; Molecular Sequence Data; Orchiectomy; Ovariectomy; Rats; Rats, Inbred SHR; Renin; RNA, Messenger; Sex Characteristics; Testosterone

Plasma renin activity varies with the level of dietary protein, being higher on a high protein diet. To explore the molecular mechanisms underlying this relationship we first examined the effect of dietary protein on renin and angiotensinogen gene expression at the level of steady state mRNA in male Sprague-Dawley rats. Renal renin mRNA was higher on a 50% (high) compared to a 6% (low) protein diet both 3 d (9.4 +/- 1.1 vs. 5.3 +/- 0.4 pg/micrograms of total RNA; P less than 0.02) and 21 d (6.8 +/- 1.0 vs. 3.5 +/- 0.4 pg/micrograms of total RNA; P less than 0.02) after dietary change. No change occurred in either renal or liver angiotensinogen mRNA. When three levels of dietary protein were examined, renal renin mRNA was elevated on a 50% and lowered on a 6% protein diet compared to a more standard 20% protein diet. Kidney weights and renal protein, RNA, and RNA/DNA increased with the level of dietary protein reflecting protein-induced renal hypertrophy. Uninephrectomy resulted in no change in renin mRNA compared to sham operation (3.7 +/- 0.1 vs. 3.4 +/- 0.1 pg/micrograms RNA; P = NS) despite renal growth in the uninephrectomy group implicating dietary protein and not hypertrophy as the major factor for stimulating renin mRNA. In conclusion, the level of dietary protein is a novel and specific stimulus for changes in renal renin mRNA. The increased plasma renin activity on a high protein diet is due at least in part to increased renin synthesis.

Topics: Angiotensinogen; Animals; Body Weight; Dietary Proteins; Gene Expression; Immunoblotting; Kidney; Male; Nephrectomy; Rats; Rats, Inbred Strains; Renin; RNA, Messenger

This study examines the role of gluco- and mineralcorticoids in the regulation of the renin-angiotensin system and blood pressure in the spontaneously hypertensive rat (SHR). Effects of adrenalectomy and selective treatment with either aldosterone (30 micrograms/kg/day) or dexamethasone (60 micrograms/kg/day) on plasma renin substrate, active renin (PRA), total renin and blood pressure were studied in 10 week old SHR and control WKY rats. Systolic blood pressure was moderately lower in adrenalectomized rats (129 +/- 2 mm Hg vs 137 +/- 4 mm Hg in control WKY and 145 +/- 4 mm Hg vs 160 +/- 3 mm Hg in control SHR) but could be restored to the control range by aldosterone. Dexamethasone repletion induced substantial increments of systolic blood pressure to comparable levels in both species (202 +/- 8 mm Hg in WKY and 192 +/- 6 mm Hg in SHR). Renin substrate was markedly lower in adrenalectomized, saline repleted rats. This could be reversed by dexamethasone in both species and by aldosterone in WKY rats only. Both PRA and total renin were higher (p less than 0.01) in the adrenalectomized, saline repleted state. This increase was not observed in aldosterone repleted rats. However, dexamethasone inhibited the adrenalectomy associated increase of PRA and total renin in SHR but not in WKY rats. Differences in blood pressure between SHR and WKY persist even in adrenalectomized state despite comparable stimulation of the renin system. Conversely, while blood pressure of both species responds similarly to selective corticosteroids therapy, the response of the renin-angiotensin system in SHR and WKY rats is distinct. Therefore factors other than the adrenal gland and the renin system must be involved in the determination of the high blood pressure in SHR.

Topics: Adrenal Cortex Hormones; Adrenal Glands; Adrenalectomy; Aldosterone; Angiotensinogen; Animals; Blood Pressure; Body Weight; Dexamethasone; Hypertension; Male; Rats; Rats, Inbred Strains; Renin-Angiotensin System

The effects of angiotensin II, thyroxine and 17 beta estradiol on plasma renin substrate concentration in rats and renin substrate production by perfused rat livers were investigated. The addition of angiotensin II (1-10 microgram) to the perfusion system did not affect the synthesis of renin substrate. After treatment with thyroxine (2.5 mg/kg/day), plasma renin substrate concentration, plasma renin activity, plasma aldosterone concentration and the rate of renin substrate synthesis were all significantly increased. 17 beta estradiol (2 mg) raised both plasma renin substrate concentration and the amount of renin substrate production by the liver. Isoelectric focusing profiles of renin substrate of liver perfusate and of plasma from estrogen-treated rats were different from that of liver perfusate from normal rats. But the profile of renin substrate in plasma was essentially similar to those to liver perfusates both in normal and estrogen-treated rats.

Topics: Angiotensin II; Angiotensinogen; Angiotensins; Animals; Body Weight; Estrogens; Female; Isoelectric Focusing; Liver; Rats; Rats, Inbred Strains; Thyroxine

Most of the 52 patients on maintenance dialysis investigated in this study suffered from arterial hypertension in spite of efforts to reduce 'dry weight'. In this situation we found that the majority of patients were underweight and that total body water, extracellular volume and blood volume were close to normal when related to reference systems consisting of height and age. Hypertensive patients were not volume expanded as compared to normotensive patients and controls. Plasma renin activity and angiotensin II were elevated in a few patients, with a trend to higher levels in the more hypertensive patients. Various approaches attempting to correlate blood pressure and the respective volume-renin factors did not prove to be conclusive in explaining the maintenance of hypertension in chronic renal failure on the basis of the sodium-renin feedback.

Topics: Adult; Aged; Angiotensin II; Angiotensinogen; Blood Pressure; Body Fluid Compartments; Body Water; Body Weight; Extracellular Space; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renin

Topics: Aldosterone; Angiotensin II; Angiotensinogen; Animals; Body Weight; Castration; Female; Male; Rats; Renin; Testosterone

1) To clarify the role of adrenal enucleation on plasma renin activity (PRA), plasma renin substrate (PRS), PRA response to furosemide administration and vacular reaction to renin in adrenal regeneration hypertension (ARH), serial changes of PRA and PRS during adrenal regeneration, PRA response to furosemide administration, and pressor response to exogenous renin in ARH were investigated by comparison with those of intact rats, unilaterally adrenalectomized rats, and unilaterally nephroadrenalectomized rats with contralateral adrenalectomy or with contralateral adrenal exploration (control) on both tap water and high sodium intake. 2) The control rats drinking saline, when compared with intact rats drinking tap water, showed significant decreases in PRA and, concomitantly, significant increases in PRS throughout the experimental period. In the unilaterally nephroadrenalectomized rats drinking saline, two days after adrenal enucleation or adrenalectomy, a significant increase in PRA, with a concomitant decrease in PRS, was observed. Those changes were less pronounced in the adrenal enucleated group than in the adrenalectomized group. Ten days later PRA markedly decreased to the control level in both groups. PRS rose to the control level on the 10th day after adrenal enucleation without increasing further, while that in the adrenalectomized group remained as low as before. 3) No significant differences in any of the experimental groups were found in diuresis, natriuresis, or in changes in body weight and hematocrit during the one and a half hours after furosemide administration performed at the 9th experimental week. The basal PRA was significantly decreased in the other groups with unilateral nephroadrenalectomy and/or a high sodium intake as compared with the unilaterally adrenalectomized rats drinking tap water. The decrease in basal PRA was much more pronounced in the unilaterally nephroadrenalectomized rats drinking saline, with or without adrenal enucleation. After furosemide administration, PRA significantly increased in the unilaterally adrenalectomized rats drinking saline as well as in the unilaterally nephroadrenalectomized rats drinking tap water, with or without adrenal enucleation, while PRA values in three groups were only a half of the unilaterally adrenalectomized rats drinking tap water. An insignificant increase was found in the unilaterally nephroadrenalectomized rats drinking saline, independent of adrenall enucleation. 4) Pressor respo

Topics: Adrenal Glands; Adrenal Medulla; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Body Weight; Female; Furosemide; Hypertension; Kidney; Male; Organ Size; Potassium; Rats; Regeneration; Renin; Sodium; Sodium Chloride

Topics: Adolescent; Adult; Age Factors; Aldosterone; Angiotensin II; Angiotensinogen; Body Weight; Contraceptives, Oral; Diuresis; Estrogens; Female; Hemodynamics; Humans; Hypertension; Natriuresis; Pituitary-Adrenal System; Renin; Sodium; Sympathetic Nervous System

The effect of actinomycin-D on blood pressure and the renin-angiotensin system has been studied in the rat. Treatment with the drug caused blood pressure, plasma renin activity and plasma renin substrate level to decrease. The results suggest that in the blood pressure-decreasing effect a reduction of the activity of the renin-angiotensin system had a role. This contradicts the view that actinomycin-D has no influence on renin production in the kidney.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Body Weight; Dactinomycin; Heart; Kidney; Male; Organ Size; Rats; Renin