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Association of elevated urinary concentration of renin-angiotensin system components and severe AKI.
Alge JL, Karakala N, Neely BA, Janech MG, Tumlin JA, Chawla LS, Shaw AD, Arthur JM, SAKInet Investigators
(2013) Clin J Am Soc Nephrol 8: 2043-52
MeSH Terms: Acute Kidney Injury, Aged, Angiotensinogen, Area Under Curve, Biomarkers, Cardiac Surgical Procedures, Chi-Square Distribution, Creatinine, Disease Progression, Female, Hospital Mortality, Humans, Logistic Models, Male, Middle Aged, Multivariate Analysis, Predictive Value of Tests, Prognosis, ROC Curve, Renin, Renin-Angiotensin System, Retrospective Studies, Risk Factors, Severity of Illness Index, United States, Up-Regulation
Show Abstract · Added June 29, 2015
BACKGROUND - Prognostic biomarkers that predict the severity of AKI at an early time point are needed. Urinary angiotensinogen was recently identified as a prognostic AKI biomarker. The study hypothesis is that urinary renin could also predict AKI severity and that in combination angiotensinogen and renin would be a strong predictor of prognosis at the time of AKI diagnosis.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - In this multicenter, retrospective cohort study, urine was obtained from 204 patients who developed AKI after cardiac surgery from August 2008 to June 1, 2012. All patients were classified as having Acute Kidney Injury Network (AKIN) stage 1 disease by serum creatinine criteria at the time of sample collection. Urine output was not used for staging. Urinary angiotensinogen and renin were measured, and the area under the receiver-operating characteristic curve (AUC) was used to test for prediction of progression to AKIN stage 3 or in-hospital 30-day mortality. These biomarkers were added stepwise to a clinical model, and improvement in prognostic predictive performance was evaluated by category free net reclassification improvement (cfNRI) and chi-squared automatic interaction detection (CHAID).
RESULTS - Both the urinary angiotensinogen-to-creatinine ratio (uAnCR; AUC, 0.75; 95% confidence interval [CI], 0.65 to 0.85) and the urinary renin-to-creatinine ratio (uRenCR; AUC, 0.70; 95% CI, 0.57 to 0.83) predicted AKIN stage 3 or death. Addition of uAnCR to a clinical model substantially improved prediction of the outcome (AUC, 0.85; cfNRI, 0.673), augmenting sensitivity and specificity. Further addition of uRenCR increased the sensitivity of the model (cfNRI(events), 0.44). CHAID produced a highly accurate model (AUC, 0.91) and identified the combination of uAnCR >337.89 ng/mg and uRenCR >893.41 pg/mg as the strongest predictors (positive predictive value, 80.4%; negative predictive value, 90.7%; accuracy, 90.2%).
CONCLUSION - The combination of urinary angiotensinogen and renin predicts progression to very severe disease in patients with early AKI after cardiac surgery.
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26 MeSH Terms
Urinary angiotensinogen predicts adverse outcomes among acute kidney injury patients in the intensive care unit.
Alge JL, Karakala N, Neely BA, Janech MG, Velez JC, Arthur JM, SAKInet Investigators
(2013) Crit Care 17: R69
MeSH Terms: Acute Kidney Injury, Adult, Aged, Aged, 80 and over, Angiotensinogen, Biomarkers, Female, Humans, Intensive Care Units, Male, Middle Aged, Predictive Value of Tests
Show Abstract · Added June 29, 2015
INTRODUCTION - Acute kidney injury (AKI) is commonly observed in the intensive care unit (ICU), where it can be caused by a variety of factors. The objective of this study was to evaluate the prognostic value of urinary angiotensinogen, a candidate prognostic AKI biomarker identified in post-cardiac surgery patients, in this heterogeneous population.
METHODS - Urinary angiotensinogen was measured by ELISA and corrected for urine creatinine in 45 patients who developed AKI in the ICU. Patients were grouped by AKI etiology, and the angiotensinogen-to-creatinine ratio (uAnCR) was compared among the groups using the Kruskal-Wallis test. The ability of uAnCR to predict the following endpoints was tested using the area under the ROC curve (AUC): the need for renal replacement therapy (RRT) or death, increased length of stay (defined as hospital discharge>7 days or death≤7 days from sample collection), and worsening AKI (defined as an increase in serum creatinine>0.3 mg/dL after sample collection or RRT).
RESULTS - uAnCR was significantly elevated in patients who met the composite outcome RRT or death (89.4 vs 25.4 ng/mg; P=0.01), and it was a strong predictor of this outcome (AUC=0.73). Patients with uAnCR values above the median for the cohort (55.21 ng/mg) had increased length of stay compared to patients with uAnCR≤55.21 ng/mg (22 days vs 7 days after sample collection; P=0.01). uAnCR was predictive of the outcome increased length of stay (AUC=0.77). uAnCR was also a strong predictor of worsening of AKI (AUC=0.77). The uAnCR of patients with pre-renal AKI was lower compared to patients with AKI of other causes (median uAnCR 11.3 vs 80.2 ng/mg; P=0.02).
CONCLUSIONS - Elevated urinary angiotensinogen is associated with adverse events in AKI patients in the ICU. It could be used to identify high risk patients who would benefit from timely intervention that could improve their outcomes.
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12 MeSH Terms
Urinary angiotensinogen and risk of severe AKI.
Alge JL, Karakala N, Neely BA, Janech MG, Tumlin JA, Chawla LS, Shaw AD, Arthur JM, SAKInet Investigators
(2013) Clin J Am Soc Nephrol 8: 184-93
MeSH Terms: Acute Kidney Injury, Aged, Angiotensinogen, Biomarkers, Female, Humans, Male, Middle Aged, Prognosis, Risk, Severity of Illness Index
Show Abstract · Added October 20, 2015
BACKGROUND - Biomarkers of AKI that can predict which patients will develop severe renal disease at the time of diagnosis will facilitate timely intervention in populations at risk of adverse outcomes.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - Liquid chromatography/tandem mass spectrometry was used to identify 30 potential prognostic urinary biomarkers of severe AKI in a group of patients that developed AKI after cardiac surgery. Angiotensinogen had the best discriminative characteristics. Urinary angiotensinogen was subsequently measured by ELISA and its prognostic predictive power was verified in 97 patients who underwent cardiac surgery between August 1, 2008 and October 6, 2011.
RESULTS - The urine angiotensinogen/creatinine ratio (uAnCR) predicted worsening of AKI, Acute Kidney Injury Network (AKIN) stage 3, need for renal replacement therapy, discharge >7 days from sample collection, and composite outcomes of AKIN stage 2 or 3, AKIN stage 3 or death, and renal replacement therapy or death. The prognostic predictive power of uAnCR was improved when only patients classified as AKIN stage 1 at the time of urine sample collection (n=79) were used in the analysis, among whom it predicted development of stage 3 AKI or death with an area under the curve of 0.81. Finally, category free net reclassification improvement showed that the addition of uAnCR to a clinical model to predict worsening of AKI improved the predictive power.
CONCLUSIONS - Elevated uAnCR is associated with adverse outcomes in patients with AKI. These data are the first to demonstrate the utility of angiotensinogen as a prognostic biomarker of AKI after cardiac surgery.
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11 MeSH Terms
Overproduction of angiotensinogen from adipose tissue induces adipose inflammation, glucose intolerance, and insulin resistance.
Kalupahana NS, Massiera F, Quignard-Boulange A, Ailhaud G, Voy BH, Wasserman DH, Moustaid-Moussa N
(2012) Obesity (Silver Spring) 20: 48-56
MeSH Terms: 3T3-L1 Cells, Adipocytes, Adipose Tissue, Angiotensin-Converting Enzyme Inhibitors, Angiotensinogen, Animals, Captopril, Glucose Intolerance, Glycerolphosphate Dehydrogenase, Inflammation, Insulin Resistance, Interleukin-10, Male, Mice, Muscle, Skeletal, NF-kappa B, Obesity, Up-Regulation
Show Abstract · Added July 21, 2014
Although obesity is associated with overactivation of the white adipose tissue (WAT) renin-angiotensin system (RAS), a causal link between the latter and systemic insulin resistance is not established. We tested the hypothesis that overexpression of angiotensinogen (Agt) from WAT causes systemic insulin resistance via modulation of adipose inflammation. Glucose tolerance, systemic insulin sensitivity, and WAT inflammatory markers were analyzed in mice overexpressing Agt in the WAT (aP2-Agt mice). Proteomic studies and in vitro studies using 3T3-L1 adipocytes were performed to build a mechanistic framework. Male aP2-Agt mice exhibited glucose intolerance, insulin resistance, and lower insulin-stimulated glucose uptake by the skeletal muscle. The difference in glucose tolerance between genotypes was normalized by high-fat (HF) feeding, and was significantly improved by treatment with angiotensin-converting enzyme (ACE) inhibitor captopril. aP2-Agt mice also had higher monocyte chemotactic protein-1 (MCP-1) and lower interleukin-10 (IL-10) in the WAT, indicating adipose inflammation. Proteomic studies in WAT showed that they also had higher monoglyceride lipase (MGL) and glycerol-3-phosphate dehydrogenase levels. Treatment with angiotensin II (Ang II) increased MCP-1 and resistin secretion from adipocytes, which was prevented by cotreating with inhibitors of the nuclear factor-κB (NF-κB) pathway or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, we show for the first time that adipose RAS overactivation causes glucose intolerance and systemic insulin resistance. The mechanisms appear to be via reduced skeletal muscle glucose uptake, at least in part due to Ang II-induced, NADPH oxidase and NFκB-dependent increases in WAT inflammation.
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18 MeSH Terms
Regulation of T-cell function by endogenously produced angiotensin II.
Hoch NE, Guzik TJ, Chen W, Deans T, Maalouf SA, Gratze P, Weyand C, Harrison DG
(2009) Am J Physiol Regul Integr Comp Physiol 296: R208-16
MeSH Terms: Adoptive Transfer, Angiotensin II, Angiotensin II Type 1 Receptor Blockers, Angiotensin II Type 2 Receptor Blockers, Angiotensinogen, Animals, Autocrine Communication, Blood Pressure, Catalase, Cells, Cultured, Homeodomain Proteins, Imidazoles, Infusion Pumps, Implantable, Losartan, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidases, Peptidyl-Dipeptidase A, Polyethylene Glycols, Pyridines, Receptor, Angiotensin, Type 1, Receptor, Angiotensin, Type 2, Renin, Renin-Angiotensin System, Superoxide Dismutase, Superoxides, T-Lymphocytes, Time Factors, Tumor Necrosis Factor-alpha
Show Abstract · Added December 10, 2013
The adaptive immune response and, in particular, T cells have been shown to be important in the genesis of hypertension. In the present study, we sought to determine how the interplay between ANG II, NADPH oxidase, and reactive oxygen species modulates T cell activation and ultimately causes hypertension. We determined that T cells express angiotensinogen, the angiotensin I-converting enzyme, and renin and produce physiological levels of ANG II. AT1 receptors were primarily expressed intracellularly, and endogenously produced ANG II increased T-cell activation, expression of tissue homing markers, and production of the cytokine TNF-alpha. Inhibition of T-cell ACE reduced TNF-alpha production, indicating endogenously produced ANG II has a regulatory role in this process. Studies with specific antagonists and T cells from AT1R and AT2R-deficient mice indicated that both receptor subtypes contribute to TNF-alpha production. We found that superoxide was a critical mediator of T-cell TNF-alpha production, as this was significantly inhibited by polyethylene glycol (PEG)-SOD, but not PEG-catalase. Thus, T cells contain an endogenous renin-angiotensin system that modulates T-cell function, NADPH oxidase activity, and production of superoxide that, in turn, modulates TNF-alpha production. These findings contribute to our understanding of how ANG II and T cells enhance inflammation in cardiovascular disease.
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31 MeSH Terms
Association analysis of genes in the renin-angiotensin system with subclinical cardiovascular disease in families with Type 2 diabetes mellitus: the Diabetes Heart Study.
Burdon KP, Langefeld CD, Wagenknecht LE, Carr JJ, Freedman BI, Herrington D, Bowden DW
(2006) Diabet Med 23: 228-34
MeSH Terms: Adult, Aged, Aged, 80 and over, Angiotensinogen, Atherosclerosis, Cardiovascular Diseases, Cohort Studies, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Endothelium, Family Health, Female, Gene Frequency, Humans, Male, Middle Aged, Nitric Oxide Synthase, Peptidyl-Dipeptidase A, Polymorphism, Single Nucleotide, Receptor, Angiotensin, Type 1, Renin-Angiotensin System, Risk Factors
Show Abstract · Added February 15, 2014
AIMS - Cardiovascular disease (CVD) is a major complication of Type 2 diabetes mellitus. The renin-angiotensin system (RAS) and nitric oxide production are both important regulators of vascular function and blood pressure. Genes encoding proteins involved in these pathways are candidates for a contribution to CVD in diabetic patients. We have investigated variants of the angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin type 1 receptor (AT1R) and endothelial nitric oxide synthase (NOS3) genes for association with subclinical measures of CVD in families with Type 2 diabetes mellitus (T2DM).
METHODS - Atherosclerosis was measured by carotid intima-media thickness and calcification of the carotid and coronary arteries in 620 European Americans and 117 African Americans in the Diabetes Heart Study. Because of the role of these systems in blood pressure regulation, blood pressure was also investigated.
RESULTS - Compelling evidence of association was not detected with any of the SNPs with any outcome measures after adjustments for covariates despite sufficient power to detect relatively small differences in traits for specific genotype combinations.
CONCLUSIONS - Genetic variation of the RAS and NOS3 genes do not appear to strongly influence subclinical cardiovascular disease or blood pressure in this diabetic population.
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22 MeSH Terms
The renal lesions that develop in neonatal mice during angiotensin inhibition mimic obstructive nephropathy.
Miyazaki Y, Tsuchida S, Fogo A, Ichikawa I
(1999) Kidney Int 55: 1683-95
MeSH Terms: Actins, Angiotensin II, Angiotensin-Converting Enzyme Inhibitors, Angiotensinogen, Animals, Animals, Newborn, Apoptosis, Cell Division, Disease Models, Animal, Epidermal Growth Factor, Gene Expression Regulation, Developmental, In Situ Hybridization, In Situ Nick-End Labeling, Insulin-Like Growth Factor I, Kidney Diseases, Kidney Medulla, Kidney Pelvis, Macrophages, Mice, Mice, Knockout, Muscle, Smooth, Peptidyl-Dipeptidase A, Platelet-Derived Growth Factor, Pressure, RNA, Messenger, Transforming Growth Factor beta, Ureter, Ureteral Obstruction
Show Abstract · Added January 20, 2012
BACKGROUND - Inhibition of angiotensin action, pharmacologically or genetically, during the neonatal period leads to renal anomalies involving hypoplastic papilla and dilated calyx. Recently, we documented that angiotensinogen (Agt -/-) or angiotensin type 1 receptor nullizygotes (Agtr1 -/-) do not develop renal pelvis nor ureteral peristaltic movement, both of which are essential for isolating the kidney from the high downstream ureteral pressure. We therefore examined whether these renal anomalies could be characterized as "obstructive" nephropathy.
METHODS - Agtr1 -/- neonatal mice were compared with wild-type neonates, the latter subjected to surgical complete unilateral ureteral ligation (UUO), by analyzing morphometrical, immunohistochemical, and molecular indices. Agtr1 -/- mice were also subjected to a complete UUO and were compared with wild-type UUO mice by quantitative analysis. To assess the function of the urinary tract, baseline pelvic and ureteral pressures were measured.
RESULTS - The structural anomalies were qualitatively indistinguishable between the Agtr1 -/- without surgical obstruction versus the wild type with complete UUO. Thus, in both kidneys, the calyx was enlarged, whereas the papilla was atrophic; tubulointerstitial cells underwent proliferation and also apoptosis. Both were also characterized by interstitial macrophage infiltration and fibrosis, and within the local lesion, transforming growth factor-beta 1, platelet-derived growth factor-A and insulin-like growth factor-1 were up-regulated, whereas epidermal growth factor was down-regulated. Moreover, quantitative differences that exist between mutant kidneys without surgical obstruction and wild-type kidneys with surgical UUO were abolished when both underwent the same complete surgical UUO. The hydraulic baseline pressure was always lower in the pelvis than that in the ureter in the wild type, whereas this pressure gradient was reversed in the mutant.
CONCLUSION - The abnormal kidney structure that develops in neonates during angiotensin inhibition is attributed largely to "functional obstruction" of the urinary tract caused by the defective development of peristaltic machinery.
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28 MeSH Terms
Mechanical stretch/relaxation stimulates a cellular renin-angiotensin system in cultured rat mesangial cells.
Becker BN, Yasuda T, Kondo S, Vaikunth S, Homma T, Harris RC
(1998) Exp Nephrol 6: 57-66
MeSH Terms: Angiotensin II, Angiotensinogen, Animals, Biomechanical Phenomena, Blotting, Northern, Blotting, Southern, Cells, Cultured, Glomerular Mesangium, Mechanoreceptors, Peptidyl-Dipeptidase A, Phosphatidylinositols, Polymerase Chain Reaction, Pressure, RNA, Messenger, Rats, Receptors, Angiotensin, Renin, Renin-Angiotensin System, Stress, Mechanical
Show Abstract · Added August 19, 2013
Angiotensin II (Ang II) may play a significant role mediating intraglomerular hypertension and glomerular sclerosis. Therefore, we investigated whether a model of pressure-induced stress, mechanical stretch/relaxation, affected the renin-angiotensin system (RAS) in cultured rat mesangial cells. Type 1 Ang II receptor (AT1R) expression was assessed by 125I-Ang II binding and quantitative reverse-transcription polymerase chain reaction. Stretch/relaxation increased steady-state AT1R mRNA levels as well as specific [125I]Ang II binding. Increased AT1R expression was associated with altered AT1R signaling. Ang II (100 nM) increased total phosphoinositide hydrolysis in control cells (186 +/- 25%, n = 6; p < 0.025 vs. no treatment). However, stretch/relaxation for 48 h further augmented AT1R-mediated PI hydrolysis (293 +/- 38%, n = 6; p < 0.025 vs. Ang II treatment alone). We examined other RAS components in mesangial cells subjected to stretch/relaxation. Angiotensinogen, determined by radioimmunoassay of Ang I generation in conditioned media, increased with stretch/relaxation, and reverse-transcription polymerase chain reaction demonstrated increased angiotensinogen gene expression in stretch/relaxation-treated cells. However, renin activity and angiotensin-converting-enzyme-like activity were unaffected by stretch/relaxation. Thus, mesangial cells maintain a local RAS similar to those described in other tissues, and AT1R expression and angiotensinogen production in this cellular RAS are increased by stretch/relaxation. It is likely that mesangial cells in vivo, exposed to variations in intraglomerular pressure, may regulate their responses via a local RAS.
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19 MeSH Terms
Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption.
Okubo S, Niimura F, Matsusaka T, Fogo A, Hogan BL, Ichikawa I
(1998) Kidney Int 53: 617-25
MeSH Terms: Actins, Angiotensin II, Angiotensinogen, Animals, Atrial Natriuretic Factor, Blood Pressure, Female, Glomerular Filtration Rate, Homeostasis, In Situ Hybridization, Kidney Concentrating Ability, Kidney Glomerulus, Kidney Tubules, Male, Mice, Mice, Knockout, Proliferating Cell Nuclear Antigen, RNA, Messenger, Transforming Growth Factor beta
Show Abstract · Added January 20, 2012
Chronic volume depletion by dietary salt restriction causes marked decrease in glomerular filtration rate (GFR) with little increase in urine osmolality in angiotensinogen gene null mutant (Agt-/-) mice. Moreover, urine osmolality is insensitive to both water and vasopressin challenge. In contrast, in normal wild-type (Agt+/+) mice, GFR remains remarkably constant and urine osmolality is adjusted promptly. Changes in volume status also cause striking divergence in renal structure between Agt-/- and Agt+/+ mice. Thus, in contrast to the remarkably stable glomerular size of Agt+/+ mice, glomeruli of Agt-/- mice are atrophied during a low salt and hypertrophied during a high salt diet. Moreover, the renal papilla, a structure unique to mammals and essential for urine diluting and concentrating mechanisms, is hypoplastic in Agt-/- mice. Thus, angiotensin is essential for the two fundamental homeostatic functions of the mammalian kidney, namely stable GFR and high urine diluting and concentrating capacity during alteration in extracellular fluid (ECF) volume. This is not only accompanied by angiotensin's tonic effects on renal vasomotor tone and tubule transporters, but also accomplished through its capacity to affect the structure of both the glomerulus and the papilla directly or indirectly.
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19 MeSH Terms
Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes.
Tsuchida S, Matsusaka T, Chen X, Okubo S, Niimura F, Nishimura H, Fogo A, Utsunomiya H, Inagami T, Ichikawa I
(1998) J Clin Invest 101: 755-60
MeSH Terms: Adrenal Glands, Anesthetics, Angiotensin II, Angiotensinogen, Animals, Benzimidazoles, Blood Pressure, Imidazoles, Infusions, Intravenous, Kidney, Losartan, Mice, Mice, Knockout, Myocardium, Phenotype, Pyridines, Receptor, Angiotensin, Type 1, Receptors, Angiotensin, Saralasin, Staining and Labeling, Tetrazoles, Thiopental, Zygote, beta-Galactosidase
Show Abstract · Added January 20, 2012
Rodents are the unique species carrying duplicated angiotensin (Ang) type 1 (AT1) receptor genes, Agtr1a and Agtr1b. After separately generating Agtr1a and Agtr1b null mutant mice by gene targeting, we produced double mutant mice homozygous for both Agtr1a and Agtr1b null mutation (Agtr1a-/-; Agtr1b-/-) by mating the single gene mutants. Agtr1a-/-, Agtr1b-/- mice are characterized by normal in utero survival but decreased ex utero survival rate. After birth they are characterized by low body weight gain, marked hypotension, and abnormal kidney morphology including delayed maturity in glomerular growth, hypoplastic papilla, and renal arterial hypertrophy. These abnormal phenotypes are quantitatively similar to those found in mutant mice homozygous for the angiotensinogen gene (Agt-/-), indicating that major biological functions of endogenous Ang elucidated by the abnormal phenotypes of Agt-/- are mediated by the AT1 receptors. Infusion of Ang II, AT1 blockers, or an AT2 blocker was without effect on blood pressure in Agtr1a-/-; Agtr1b-/- mice, indicating that AT2 receptor does not exert acute depressor effects in these mice lacking AT1 receptors. Also, unlike Agt-/- mice, some Agtr1a-/-; Agtr1b-/- mice have a large ventricular septum defect, suggesting that another receptor such as AT2 is functionally activated in Agtr1a-/-, Agtr1b-/- mice.
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24 MeSH Terms