angiotensinogen and Proteinuria

Topics: Angiotensinogen; Animals; Humans; Hypertrophy; Kidney; Kidney Tubules; Peptidyl-Dipeptidase A; Proteinuria; Receptors, Angiotensin; Renal Circulation; Renal Insufficiency; Renin; Renin-Angiotensin System; Sclerosis

Activation of the rennin-angiotensin system (RAS) is thought to contribute to hypertension and proteinuria, and eventually to the progression of chronic kidney disease (CKD). Recent evidence suggests that urinary angiotensinogen (UAGT) excretion reflects activation of the intrarenal RAS. This study was performed to determine the effect of losartan on proteinuria and UAGT excretion in non-diabetic patients with CKD with non-nephrotic-range proteinuria.. Thirty-two patients with non-nephrotic-range proteinuria (0.045-0.23 g/mmol creatinine) and normal renal function between April 2005 and April 2006 were randomised to a losartan (n=17) or a control (n=15) group. Patients in the losartan group received losartan 50 mg/day, and the doses were titrated up to 100 mg/day after 6 weeks. Serum and urinary angiotensinogen concentrations were measured by sandwich ELISA. The primary end point was the percentage change in proteinuria. The secondary end points were changes in estimated glomerular filtration rate and UAGT excretion. The follow-up period was 24 months.. Baseline characteristics in the two groups were similar. After 24 months, losartan had reduced urinary protein excretion by 43% (from mean±SD 0.13±0.04 to 0.073±0.03 g/mmol, p<0.0001), but proteinuria had not changed in the control group. The percentage change in mean arterial pressure did not differ between the groups. Losartan decreased logarithmically converted UAGT excretion (from 1.58±0.47 to 1.00±0.52, p=0.001). Estimated glomerular filtration rate decreased significantly only in the control group.. Losartan significantly decreased proteinuria and UAGT excretion, and preserved renal function in non-diabetic patients with CKD.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Losartan; Male; Middle Aged; Proteinuria; Renin-Angiotensin System

Augmentation of intrarenal angiotensinogen (AGT) leads to further formation of intrarenal angiotensin II (Ang II) and the development of hypertensive kidney injury. Recent studies demonstrated that macrophages and the enhanced production of pro-inflammatory cytokines can be crucial mediators of renal AGT augmentation in hypertension. Accordingly, this study investigated the effects of immunosuppression by mycophenolate mofetil (MMF) on intrarenal AGT augmentation. Ang II (80 ng/min) was infused with or without daily administration of MMF (50 mg/kg) to Sprague-Dawley rats for 2 weeks. Mean arterial pressure (MAP) in Ang II infused rats was slightly higher (169.7 ± 6.1 mmHg) than the Ang II + MMF group (154.7 ± 2.0 mmHg), but was not statistically different from the Ang II + MMF group. MMF treatment suppressed Ang II-induced renal macrophages and IL-6 elevation. Augmentation of urinary AGT by Ang II infusion was attenuated by MMF treatment (control: 89.3 ± 25.2, Ang II: 1194 ± 305.1, and Ang II + MMF: 389 ± 192.0 ng/day). The augmentation of urinary AGT by Ang II infusion was observed before the onset of proteinuria. Elevated intrarenal AGT mRNA and protein levels in Ang II infused rats were also normalized by the MMF treatment (AGT mRNA, Ang II: 2.5 ± 0.2 and Ang II + MMF: 1.5 ± 0.1, ratio to control). Ang II-induced proteinuria, mesangial expansion and renal tubulointerstitial fibrosis were attenuated by MMF. Furthermore, MMF treatment attenuated the augmentation of intrarenal NLRP3 mRNA, a component of inflammasome. These results indicate that stimulated cytokine production in macrophages contributes to intrarenal AGT augmentation in Ang II-dependent hypertension, which leads to the development of kidney injury.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Hypertension; Immunosuppression Therapy; Kidney; Kidney Diseases; Mycophenolic Acid; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger

Although urinary angiotensinogen (AGT) and renin reflect intrarenal renin-angiotensin system activity and are enhanced in proteinuric chronic kidney disease, the clinical value of urinary AGT and renin levels during antiproteinuric treatment has yet to be determined. We investigated the clinical usefulness of initial urinary AGT or renin to determine the antiproteinuric effects of angiotensin receptor blockers (ARBs).. This multicenter, prospective, single-arm study included 205 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] ≥ 1 mg/mg) enrolled between April 2009 and December 2011. All patients were treated with valsartan. The urinary AGT/creatinine ratio (uAGT/Cr) was measured at the baseline and 24 weeks, and the renin/creatinine ratio (uR/Cr) was measured at the baseline. Fifty-six patients were followed-up for 5 years.. Our study demonstrates the potential role of both baseline urinary AGT and changes in urinary AGT during the initial 24 weeks as surrogate markers predicting the antiproteinuric effects of ARBs in patients with overt proteinuria.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Female; Humans; Male; Middle Aged; Prognosis; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Treatment Outcome; Valsartan

Immunosuppressive treatment will predispose an idiopathic membranous nephropathy (iMN) patient to opportunistic infections. Disease severity is one of the main concerns for making the treatment decision. Urinary angiotensinogen (UAGT) level has been shown highly correlated with intrarenal renin-angiotensin system (RAS) activity and severity of chronic kidney diseases (CKD). We aimed to test the relationship between the UAGT level and the severity of iMN.. This cross-sectional study included a total of 48 biopsy-proven iMN patients, 46 minimal change disease (MCD) patients, and 44 healthy volunteers. The clinical and laboratory data and urine samples were collected from all subjects before the use of RAS inhibitors. We determined the UAGT levels with a method of enzyme-linked immunosorbent assay.. The UAGT levels were not different between the iMN (277.05 ± 61.25, μg/g.Cr) and MCD patients (244.19 ± 40.24, μg/g.Cr), but both of them were significantly higher than those of healthy controls (6.85 ± 1.10, μg/g.Cr). UAGT levels were correlated negatively with serum albumin (r = - 0.393, p = 0.006) and estimated glomerular filtration rate (eGFR) (r = - 0.352, p = 0.014) and positively with 24-h proteinuria (r = 0.614, p < 0.001) in iMN patients but not in MCD patients. Multivariate linear regression analysis revealed that only proteinuria independently determinate the levels of UAGT (β = 0.649, p < 0.001) in iMN patients.. UAGT levels were correlated negatively with serum albumin and glomerular filtration rate and positively with proteinuria in iMN patients at the onset. This suggests that elevated levels of UAGT are associated with the severity of iMN. The UAGT level may be used as a cofactor for deciding immunosuppressive therapy in iMN patient.

Topics: Adolescent; Adult; Aged; Angiotensinogen; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Humans; Middle Aged; Nephrosis, Lipoid; Proteinuria; Serum Albumin; Severity of Illness Index; Young Adult

Urinary protein (UP) is widely used as a clinical marker for podocyte injury; however, not all proteinuric nephropathies fit this model. We previously described the elevation of urinary angiotensinogen (AGT) accompanied by AGT expression by injured podocytes in a nitric oxide inhibition rat model (Eriguchi M, Tsuruya K, Haruyama N, Yamada S, Tanaka S, Suehiro T, Noguchi H, Masutani K, Torisu K, Kitazono T. Kidney Int 87: 116-127, 2015). In this report, we performed the human and animal studies to examine the significance and origin of urinary AGT. In the human study, focal segmental glomerulosclerosis (FSGS) patients presented with higher levels of urinary AGT, corrected by UP, than minimal-change disease (MCD) patients. Furthermore, AGT was evident in podocin-negative glomerular segmental lesions. We also tested two different nephrotic models induced by puromycin aminonucleoside in Wistar rats. The urinary AGT/UP ratio and AGT protein and mRNA expression in sieved glomeruli from FSGS rats were significantly higher than in MCD rats. The presence of AGT at injured podocytes in FSGS rats was detected by immunohistochemistry and immunoelectron microscopy. Finally, we observed the renal tissue and urinary metabolism of exogenous injected human recombinant AGT (which is not cleaved by rodent renin) in FSGS and control rats. Significant amounts of human AGT were detected in the urine of FSGS rats, but not of control rats. Immunostaining for rat and human AGT identified that only rat AGT was detected in injured podocytes, and filtered human AGT was seen in superficial proximal tubules, but not in injured podocytes, suggesting AGT generation by injured podocytes. In conclusion, the urinary AGT/UP ratio represents a novel specific marker of podocyte injury.

Topics: Adult; Aged; Angiotensinogen; Animals; Antibiotics, Antineoplastic; Female; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Tubules, Proximal; Male; Middle Aged; Nephrosis, Lipoid; Podocytes; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Wistar

Maternal vitamin D deficiency is proposed as a risk factor for preeclampsia in humans. We tested the hypothesis that vitamin D depletion aggravates and high supplementation ameliorates the preeclampsia phenotype in an established transgenic rat model of human renin-angiotensin system-mediated preeclampsia. Adult rat dams, transgenic for human angiotensinogen (hAGT) and mated with male rats transgenic for human renin (hREN), were fed either vitamin D-depleted chow (VDd) or enriched chow (VDh) 2 weeks before mating and during pregnancy. Mean blood pressure was recorded by tail-cuff, and 24-hour urine samples were collected in metabolic cages at days 6 and 18 of gestation. Rats were sacrificed at day 21 of gestation. Depleted dams (VDd) had negligible serum 25-hydroxyvitamin D2+3 levels (mean ± SEM; 2.95 ± 0.45 nmol/l vs. VDh 26.20 ± 2.88 nmol/l, P = .01), but in both groups, levels of 1,25(OH)2D3 remained below detection level of 25 pmol/l. Dietary vitamin D depletion did not aggravate hypertension (mean ± SEM BP, day 20 of gestation: 151.38 ± 5.65 mmHg VDd vs. 152.00 ± 4.10 mmHg VDh) or proteinuria. Fetal anthropometrics were similar between the groups, whereas VDd displayed lower placental:fetal weight ratios (0.15 vs. 0.16 g/g, P = .01) and increased sFlt-1/PlGF ratio. Expression of hREN was lower in placenta of VDd dams (0.82 ± 0.44 AU vs. 1.52 ± 0.15 AU, P = .04). Expression of key vitamin D metabolizing enzymes was unchanged. Dietary vitamin D intervention did not alter key aspects of the preeclampsia phenotype using the transgenic rodent model of human renin-angiotensin system-mediated pre-eclampsia, plausibly due to altered vitamin D metabolism or excretion in the transgenic rats.

Topics: Adult; Angiotensinogen; Animals; Blood Pressure Determination; Diet; Disease Models, Animal; Female; Humans; Male; Phenotype; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renal Elimination; Renin; Renin-Angiotensin System; Risk Factors; Vitamin D; Vitamin D Deficiency

Preeclampsia is a life-threatening disorder of pregnancy. The pathogenic mechanisms of preeclampsia remain uncertain. The aim of this study is to investigate the relation between urinary angiotensinogen (UAGT) levels, an indicator of local renin-angiotensin system (RAS) activity in the kidney, and blood pressure and urinary protein excretion in preeclampsia.. For this study, 90 women aged between 20-39 years were recruited. Spot urine samples were collected to measure urinary angiotensinogen/creatinine ratio (UAGT/UCre). Log(UAGT/UCre) was compared in pregnancies with and without preeclampsia and non-pregnant controls. Factors affecting log(UAGT/UCre) in pregnancies were also investigated.. In all pregnancies log(UAGT/UCre) levels were significantly higher than in non-pregnant controls (0.58±0.19 vs. 0.33±0.14, respectively, p=0.002). However, log(UAGT/UCre) levels in pregnancies with preeclampsia were slightly lower than in normal pregnancies (0.52±0.18 vs. 0.64±0.19, respectively, p=0.012). Log(UAGT/UCre) levels were correlated positively with blood pressure and proteinuria in pregnancies with preeclampsia. However, log(UAGT/UCre) levels were not correlated with age, height, body weight, gestational age, body mass index, and serum creatinine.. This study showed that elevated local RAS activity in kidney was correlated with high blood pressure and proteinuria in preeclampsia. Local RAS activation in the kidneys may be one of the contributing factors in the development of preeclampsia.

Topics: Adult; Angiotensinogen; Blood Pressure; Creatinine; Demography; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Proteinuria; Systole; Young Adult

The intrarenal renin-angiotensin system (RAS) has been reported to be activated in chronic proteinuria patients. This study aimed to compare intrarenal RAS activity between diabetic nephropathy (DN) and non-diabetic nephropathy (NDN) patients with overt proteinuria.. A multicenter, cross-sectional study was conducted in 116 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] > 1 mg/mg Cr). To estimate intrarenal RAS activity we measured urinary excretion of angiotensinogen (uAGT) and renin (uRenin) in patients with DN (n = 38) and NDN (n = 78).. Both natural logarithms of uAGT/urinary creatinine (ln[uAGT/uCr]) and uRenin (ln[uRenin/uCr]) levels were significantly higher in patients with DN compared with those with NDN (ln[uAGT/uCr]: 4.16 ± 1.13 in DN vs. 3.52 ± 1.21 in NDN, P = 0.007; ln[uRenin/uCr]: 5.66 ± 1.60 in DN vs. 4.29 ± 1.48 in NDN, P < 0.001), when estimated glomerular filtration rate (eGFR) and uPCR showed no significant difference between the two groups. In a subgroup analysis, according to amount of proteinuria, both uAGT and uRenin were higher in DN in patients with subnephrotic-range proteinuria (uPCR < 3.5 mg/mg Cr). However, in patients with nephrotic-range proteinuria (uPCR ≥ 3.5 mg/mg Cr), only uRenin was higher in DN compared to NDN. In a multiple regression analysis, diabetes showed independent association with uRenin.. Consistently elevated uRenin in DN, regardless of the amount of proteinuria, indicates that intrarenal RAS activity may be higher in DN compared to NDN in patients with overt proteinuria.

Topics: Adult; Aged; Angiotensinogen; Biomarkers; Creatinine; Cross-Sectional Studies; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Predictive Value of Tests; Proteinuria; Renin; Renin-Angiotensin System; Republic of Korea; Retrospective Studies; Up-Regulation

In the present study, we evaluated the effect of short term hyperglycemia on renal lesions in a mouse model (Tg26) of HIV-associated nephropathy (HIVAN). Control and Tg26 mice in groups (n=6) were administered either normal saline (FVBN or Tg) or streptozotocin (FVBN+STZ or Tg26+STZ). After two weeks, biomarkers were collected and kidneys were harvested. FVBN+ STZ and Tg26+STZ displayed elevated serum glucose levels when compared to FVBN and Tg26 respectively. Tg26+STZ displayed elevated (P<0.05) blood urea nitrogen (BUN) levels (P<0.05) and enhanced (P<0.01) proteinuria when compared to Tg26. Tg26+STZ displayed enhanced (P<0.001) number of sclerotic glomeruli and microcysts vs. Tg26. Renal tissues of Tg26 displayed down regulation of vitamin D receptor (VDR) expression and enhanced Ang II production when compared to FVBN mice. Hyperglycemia exacerbated down regulation of VDR and production of Ang II in FVBN and Tg mice. Hyperglycemia increased kidney cell reactive oxygen species (ROS) production and oxidative DNA damage in both FVBN and Tg26 mice. In in vitro studies, HIV down regulated podocyte VDR expression and also enhanced renin angiotensin system activation. In addition, both glucose and HIV stimulated kidney cell ROS generation and DNA damage and compromised DNA repair; however, tempol (superoxide dismutase mimetic), losartan (Ang II blocker) and EB1089 (VDR agonist) provided protection against DNA damaging effects of glucose and HIV. These findings indicated that glucose activated the RAS and inflicted oxidative stress-mediated DNA damage via down regulation of kidney cell VDR expression in HIV milieu both in vivo and in vitro.

Topics: AIDS-Associated Nephropathy; Angiotensinogen; Animals; Cells, Cultured; Down-Regulation; gag Gene Products, Human Immunodeficiency Virus; Glucose; HEK293 Cells; HIV-1; Humans; Hyperglycemia; Kidney Glomerulus; Mice; Mice, Transgenic; Podocytes; pol Gene Products, Human Immunodeficiency Virus; Proteinuria; Reactive Oxygen Species; Receptors, Calcitriol; Streptozocin

The renin-angiotensin system (RAS) is thought to regulate blood pressure and to be an independent risk factor for the development of left ventricular hypertrophy (LVH) and carotid intima-media thickness (CIMT). Locally produced RAS in most tissues has been recently described. It has been reported that urinary angiotensinogen levels provide a specific index of the intrarenal RAS status and is significantly correlated with blood pressure and proteinuria. The aim of this study was to evaluate the relationship of local intrarenal RAS with LVH and CIMT in hypertensive renal transplant recipients (RTRs).. A total of 96 non-diabetic RTRs (50 hypertensive patients, 46 normotensive patients) were included in this study. Urinary angiotensinogen (UAGT)/urinary creatinine (Ucre) was significantly higher in hypertensive patients compared with normotensive patients (p < 0.01). Left ventricular mass (LVM)I and CIMT were significantly higher in hypertensive patients compared with the normotensive patients (p < 0.01). Importantly, a significant positive correlation was found between UAGT/Ucre levels and LVMI (r = 0.724, p = 0.012) and also CIMT (r = 0.452, p = 0.02) in hypertensive RTRs.. These data indicate that UAGT is increased in hypertensive RTRs, and local RAS may play an important role in the development of cardiovascular abnormalities in hypertensive renal transplant recipients.

Topics: Angiotensinogen; Blood Pressure Monitoring, Ambulatory; Carotid Intima-Media Thickness; Case-Control Studies; Creatinine; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Survival; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Proteinuria; Renin-Angiotensin System; Risk Factors; Transplant Recipients

To test the hypothesis that in a high-salt induced hypertension in normal rats, whether the changes of intrarenal renin-agiotensin system (RAS) play a critical role in renal damage and could be reflected by urinary angiotensinogen (AGT).. In the study, 27 normotensive male Wistar-Kyoto rats were divided into control group [0.3% (mass faction) NaCl in chow, n=9, NS], high-salt diet group [8% (mass faction) NaCl in chow, n=9, HS] and high-salt diet with Losartan group [8% (mass faction) NaCl in chow and 20 mg/(kg×d) Losartan in gavages, n=9, HS+L)], and were fed for six weeks. The blood pressure was monitored and urine samples were collected every 2 weeks. AGTs in plasma, kidney and urine were measured by ELISA kits. The renal cortex expression of mRNA and protein of AGT were measured by Real-time PCR and immunohistochemistry (IHC). The renin activity and ANG II were measured by radioimmunoassay (RIA) kits.. Compared with NS, the systolic blood pressure (SBP) [(156 ± 2) mmHg vs. (133 ± 3) mmHg, P<0.05] increased significantly at the end of the 2nd week, and the urinary protein [(14.07 ± 2.84) mg/24 h vs. (7.62 ± 3.02) mg/24 h, P<0.05] increased significantly at the end of the 6th week in HS. Compared with HS, there was no significant difference in SBP (P>0.05) but the proteinuria [(9.69 ± 2.73) mg/24 h vs. (14.07 ± 2.84) mg/24 h, P<0.01] decreased significantly in HS+L. Compared with NS, there was no significant difference in the plasma renin activity, angiotensinogen and ANG II level in HS (P>0.05), but the renal cortex renin content [(8.72 ± 1.98) ng/(mL × h) vs. (4.37 ± 1.26) ng/(mL × h), P<0.05], AGT formation [(4.02 ± 0.60) ng/mg vs. (2.59 ± 0.42) ng/mg, P<0.01], ANG II level [(313.8 ± 48.76) pmol/L vs. (188.9 ± 46.95) pmol/L, P<0.05] were increased significantly in HS, and the urinary AGT and ANG II excretion rates increased significantly (P<0.05). Compared with HS, the plasma renin activity, angiotensinogen and ANG II level were significantly increased (P<0.05), but the renal cortex renin content, AGT formation, ANG II level significantly decreased (P<0.05), and the urinary AGT and ANG II excretion rates decreased significantly in HS+L (P<0.05). The urinary AGT excretion rates were positively correlated with the AGT level in the renal cortex (P<0.05).. Up-regulation of intarenal RAS may contribute to renal damage in high-salt induced hypertension rats. Urinary AGT may reflect the status of intrarenal RAS.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Hypertension; Kidney; Male; Proteinuria; Rats; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary; Up-Regulation

Few studies have addressed the growing concerns of chronic kidney diseases in children with intrauterine growth restriction (IUGR). Therefore, the purpose of this study was to evaluate long-term kidney dysfunction and determine if urinary angiotensinogen (AGT) was suitable as a novel early biomarker for kidney dysfunction in IUGR offspring.. Pregnant rats underwent bilateral uterine artery ligation, and as a control group, sham surgeries were performed.. The birth weight was reduced, the urinary AGT to creatinine ratio was significantly higher at week 20, and urinary protein levels were significantly higher at week 32 in IUGR rats than in control rats. On the other hand, the histological findings at week 32 revealed long-term kidney dysfunction, more severe glomerulosclerosis, and greater glomerular diameters in IUGR rats. Moreover, AGT mRNA expression and immunohistological staining were significantly increased in IUGR rats; this suggests that the intrarenal renin-angiotensin system (RAS) contributes to renal dysfunction of IUGR offspring.. Urinary AGT elevation prior to urinary protein levels suggests that AGT is an early biomarker. At week 32, kidney dysfunction was severe in IUGR rats and intrarenal RAS appeared to be one of the causes.

Topics: Age Factors; Angiotensinogen; Animals; Biomarkers; Birth Weight; Creatinine; Disease Models, Animal; Early Diagnosis; Female; Fetal Growth Retardation; Kidney; Kidney Diseases; Ligation; Organ Size; Predictive Value of Tests; Pregnancy; Prenatal Exposure Delayed Effects; Proteinuria; Rats, Sprague-Dawley; Renin-Angiotensin System; Up-Regulation; Uterine Artery

It had been reported that angiotensinogen might be a marker for activation of renin-angiotensin system, which was associated with the development of diabetic nephropathy. The purpose of this study was to investigate the functional roles of AGT in DN in vitro.. Diabetic rat models were built by single intraperitoneal injection of streptozotocin. The diabetic rats were divided into three groups, two of the three groups were treated with different doses of losartan, the other diabetic group was as control and normal rats acted as healthy control. In a 12-week investigation, we detected the changes of AGT in all rats' blood and urine and the association between AGT concentration and RAS activation and urinary proteins were analyzed in this study.. The serum AGT of rats had no significant differences (P>0.05 for all). The urinary AGT of the diabetic rats was significantly different from the control group, moreover, the urinary AGT of the diabetic rats under different treatments was also obviously different (P<0.05 for all). Besides, the results of immunohistochemical assay indicated that AGT expression level was correlated with renal tissues damage. The level of AGT was positively associated with urinary protein (r=0.493, P<0.01) and negatively correlated with CCr (r=-0.474, P=0.007) and the dose of ARB (r=-0.575, P=0.001). Moreover, the dose of ARB was independently associated with urinary AGT (B=-2.963, P=0.024) in diabetic rats.. Urinary AGT may be a marker for the activation of local RAS in kidney and independently associated with ARB.

Topics: Angiotensinogen; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Kidney; Male; Proteinuria; Rats; Rats, Sprague-Dawley

Urinary angiotensinogen (AGT) and renin have been reported to reflect the intrarenal renin-angiotensin system (RAS) activity. However, the adequacy and clinical significance of these markers have not been evaluated in overtly proteinuric patients. In patients with biopsy-proven glomerulonephritis, plasma and urinary AGT and renin were analyzed. A cohort of 75 patients treated with RAS inhibitors was followed for 1 year. Among the 207 patients, 105 had subnephrotic and 102 had nephrotic-range proteinuria. Mean age, estimated glomerular filtration rate (eGFR), and urinary protein-to-creatinine ratio (P/Cr) of all patients were 48 years, 79.7 mL/min/1.73 m(2), and 5.66 mg/mg, respectively. Both natural logarithm of urinary AGT/creatinine (ln [urinary AGT/Cr]) and ln (urinary renin/Cr) showed positive correlations with urinary P/Cr. There was a positive correlation between ln (urinary AGT/Cr) and ln (urinary renin/Cr). Ln (urinary renin/Cr) was not affected by ln (plasma renin) regardless of the degree of proteinuria. The treatment response to RAS inhibitors was greatest in patients with high urinary AGT and renin. However, the predictive value of those parameters was no longer present when the values were adjusted by the degree of proteinuria. Ln (urinary renin/Cr) and initial eGFR were independently associated with the changes in renal function for 1 year. Ln (urinary AGT/Cr) was associated with persistent overt proteinuria after 1 year. Our study suggests that urinary renin may be a better marker in heavy proteinuria, and the treatment response to RAS inhibitors may be enhanced in patients with high urinary renin and AGT. Further studies will be necessary to explore the value of urinary AGT and renin.

Topics: Adult; Aged; Angiotensinogen; Biomarkers; Female; Humans; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System

The urinary angiotensinogen (AGT) excretion rate could be a novel biomarker for the intrarenal activity of the renin-angiotensin system. Little is known about the circadian rhythm of AGT levels in plasma or urine. In this short article, making use of data in plasma and urine of healthy volunteers and patients with chronic kidney diseases, we first report that we were unable to find evidence for a circadian rhythm of AGT under any condition. Next we critically discuss to what degree elevated urinary AGT levels might be considered an independent biomarker that is not simply the non-specific consequence of proteinuria.

Topics: Adult; Angiotensin I; Angiotensinogen; Biomarkers; Circadian Rhythm; Enzyme-Linked Immunosorbent Assay; Female; Healthy Volunteers; Humans; Male; Proteinuria; Renal Insufficiency, Chronic

To investigate the change of intrarenal renin-agiotensin system (RAS) and its role in high-salt induced hypertension.. Wistar rats were divided into normal-salt (NS), high-salt diet (HS) and high-salt diet with Losartan group (HS+L), for 6 weeks. Systolic blood pressure (SBP) was monitored. Blood and urine samples were collected every 2 weeks. Angiotensinogen (AGT) was measured by ELISA. AGT mRNA and protein were measured by real-time PCR and immunohistochemistry. Renin activity and angiotensin II (Ang II) were measured by radioimmunoassay.. HS versus NS group, SBP increased from 2(nd) week (P<0.05), urinary protein increased at 6(th) week (P<0.05). Although plasma renin, AGT and Ang II had no significant changes (P>0.05), renal cortex renin, AGT, and Ang II increased significantly in HS (P<0.05). In HS+L, Losartan failed to reduce SBP (P>0.05) but abolished the increase of proteinuria (P<0.01), renal cortex renin, AGT, Ang II and urinary AGT reduced (P<0.05) while plasma renin, AGT and Ang II enhanced (P<0.05) when compared with HS. Urinary AGT was positively correlated with renal AGT (r=0.592, P <0.01) and Ang II (r=0.726, P <0.01).. Inappropriate response of the renal RAS to a high salt diet may contribute to hypertension and renal damage, and urinary AGT could reflect intrarenal RAS activity.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Diet; Hypertension, Renal; Kidney; Losartan; Male; Proteinuria; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; RNA, Messenger; Sodium Chloride, Dietary; Up-Regulation

Along with immunologic mechanisms, intrarenal renin-angiotensin system (RAS) activation has been suggested to play a role in the development and progression of chronic allograft injury. In various glomerular diseases, urinary angiotensinogen (AGT) level is a good indicator for the activation of intrarenal RAS. In this study, we aimed to investigate the parameters associated with urinary AGT level in patients with kidney transplantation.. Seventy renal transplant patients with stable graft function (≥ 6 months after transplantation, serum creatinine level <2 mg/dL) and 21 healthy volunteers were included in the study. Patients were taking standard triple immunosuppressive treatment. Demographic characteristics of patients and healthy volunteers, drug use, and 24-hour ambulatory blood pressure measurements were recorded. Morning second urine and fasting blood samples were taken from all participants. Serum biochemical markers and urine Na, K, uric acid, creatinine, and protein levels were measured. Urinary AGT levels were determined by enzyme-linked immunosorbent assay.. Mean systolic and diastolic blood pressures in patients with renal transplantation were higher than in healthy volunteers. Both urinary AGT-urinary creatinine ratio (UAGT/UCr) and urinary protein-urinary creatinine ratio (UPro/UCr) were higher in kidney transplant patients than in healthy volunteers (P < .01; P < .0001; respectively). In patients with renal transplantation, UAGT/UCr was positively correlated with UPro/UCr and negatively correlated with estimated glomerular filtration rate (eGFR) (r = 0.738; P = .01; and r = -0.397; P = .01; respectively). There was no correlation between UAGT/UCr and other study parameters, including bood pressure levels.. Our findings indicate that high urinary excretion of AGT is associated with proteinuria and lower eGFR in kidney transplant recipients without overt chronic allograft injury. These preliminary results encourage us to design a long-term longitudinal analysis using urinary AGT along with multiple markers to obtain early diagnosis and to predict the prognosis of chronic allograft dysfunction.

Topics: Adolescent; Adult; Aged; Angiotensinogen; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Proteinuria; Young Adult

Early onset of hypertension and its consequences account for the great majority of deaths in patients with autosomal dominant polycystic kidney disease (ADPKD). Renin-angiotensin system (RAS) components have been shown in ADPKD kidneys independent of systemic RAS. Thus, we examined the urinary angiotensinogen (UAGT) levels as a biomarker of intrarenal RAS status in ADPKD patients with/without hypertension and healthy subjects.. Eighty-four ADPKD patients (43 with hypertension and 41 without hypertension) and 40 healthy controls were studied cross-sectionally. Patients with glomerular filtration rate <60 ml/min were excluded from the study. Hypertension was diagnosed with ambulatory blood pressure monitoring. Urinary and plasma concentration of angiotensinogen, spot urine microprotein and creatinine (UCre) levels were recorded for each participant.. UAGT/UCre levels were higher in hypertensive ADPKD patients (23.7 ± 8.4) compared with normotensive ADPKD patients (16.6 ± 5.2) and healthy controls (6.9 ± 3.3; p < 0.001). In univariate analysis, UAGT correlated with systolic blood pressure, diastolic blood pressure (DBP) and proteinuria. The independence of these correlations was analyzed in a regression model, and UAGT was shown to be significantly predicted by proteinuria and DBP.. Intrarenal RAS activation which is monitored by UAGT levels clinically may be a harbinger of hypertension and kidney disease in ADPKD patients.

Topics: Adult; Angiotensinogen; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Case-Control Studies; Cohort Studies; Creatinine; Cross-Sectional Studies; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Proteinuria; Regression Analysis; Renin-Angiotensin System

The purpose of our study was to evaluate the correlation of polymorphisms in angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and endothelial nitric oxide synthase (eNOS) genes and the development and prognostic implications for immunoglobulin A nephropathy (IgAN)/membranous nephropathy (MN). A polymerase chain reaction was performed for the AGT, ACE, and eNOS genes, followed by DNA sequencing and statistical analysis. There was a difference in ACE gene type II and type I between the IgAN and MN groups (P < .05) and in eNOS gene TT type and T type between the IgAN and MN groups (P < .05 and P < .01). In the IgAN group, significant differences were observed between ACE gene polymorphism and the age group of 20 years or less, male sex group, with/without hematuria, and high blood urea nitrogen (BUN; P < .05 or P < .01); between AGT gene polymorphism and with/without hematuria, high BUN, and pathologic classification (P < .05 or P < .01); and between eNOS gene polymorphism and high BUN and pathologic classification (P < .05 or P < .01). However, in the MN group, significant differences were observed between ACE gene polymorphism and the degree of proteinuria and high BUN (P < .001 and P < .05), between AGT gene polymorphism and with/without hematuria (P < .05), and between eNOS gene polymorphism and the degree of proteinuria and high BUN (P < .05 and P < .01). The ACE, AGT, and eNOS genes were correlated with the development of renal function failure in IgAN, whereas the ACE and eNOS genes were associated with the degree of proteinuria and the development of renal function failure in MN.

Topics: Adolescent; Adult; Angiotensinogen; Disease Progression; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Glomerulonephritis, IGA; Glomerulonephritis, Membranous; Humans; Kidney; Male; Middle Aged; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Proteinuria

Urinary angiotensinogen (AGT) was reported as a marker of renal injury in chronic kidney disease patients. However, the main source of urinary AGT is unknown in proteinuric patients because the disrupted filtration barrier might cause AGT filtration. We investigated the origin and the clinical importance of urinary AGT in proteinuric IgA nephropathy (IgAN) patients.. In patients with biopsy-proven IgAN, urinary and plasma AGT was measured using a sandwich ELISA and compared with intrarenal AGT expression. The patients were followed up for 3 years.. Natural logarithm of the urinary AGT/creatinine (ln (urinary AGT/Cr)) was positively correlated with intrarenal expression of AGT (ln (urinary AGT/Cr) versus AGT/β-actin, r = 0.620, P < 0.0001; ln (urinary AGT/Cr) versus AGT density, r = 0.452, P = 0.007). Ln (urinary AGT/Cr) showed a positive correlation with urinary protein/creatinine ratio (PCR) but a negative correlation with estimated glomerular filtration rate (eGFR). Regression analyses showed that ln (urinary AGT/Cr) was a significant determinant of urinary PCR and eGFR 3 years after biopsy.. Urinary AGT reflects intrarenal AGT expression and correlates with the extent of proteinuria and renal function. Our study indicates the intrarenal compartment as the main source of urinary AGT, suggesting its clinical implication as an important biomarker in proteinuric IgAN patients.

Topics: Adolescent; Adult; Angiotensinogen; Female; Follow-Up Studies; Glomerulonephritis, IGA; Humans; Male; Middle Aged; Proteinuria; Young Adult

To investigate whether urinary angiotensinogen (UAGT) levels are correlated with renal involvement of Henoch-Schonlein purpura (HSP) in children, and to explore whether UAGT has any relation to the severity of HSP.. The study sample consisted of 107 patients (50 boys and 57 girls, 6.68±2.41 years) with clinical diagnosis of HSP. A 24 h urine sample was collected before treatment. UAGT levels were measured in patients with HSP in the acute and convalescent phases by enzyme linked immunosorbent assay.. Urinary angiotensinogen/urinary concentration of creatinine levels were significantly higher in proteinuric HSP in the acute phase and the convalescent phase (32.02±3.95 and 25.31±4.11 µg/g) compared with those with HSP without renal involvement (17.26±2.60 and 15.14±3.81 µg/g) and those with hematuric HSP (19.70±2.21 and 17.28±3.62 µg/g) (P<0.0001 and P<0.01, respectively). Using matched urine samples from the same patients, UAGT/urinary concentration of creatinine (UCr) levels of proteinuric HSP patients were significantly lower in the convalescent phase (25.31 ± 4.11 µg/g, P<0.01) than in the acute phase (32.02±3.95 µg/g). UAGT/UCr levels showed positive correlation with 24 h urine protein or serum creatinine in both hematuric HSP and proteinuric HSP groups during the acute phase (P<0.05).. Urinary angiotensinogen levels were remarkably high in the acute phase in the patients with proteinuric HSP, suggesting increased UAGT may indicate a series of functional changes in the kidney and it may be used as a potential biomarker of severity of HSP to monitor the progression of HSP with renal involvement.

Topics: Acute-Phase Reaction; Angiotensinogen; Biomarkers; Child; Child, Preschool; Convalescence; Creatinine; Enzyme-Linked Immunosorbent Assay; Female; Hematuria; Humans; IgA Vasculitis; Kidney; Male; Monitoring, Physiologic; Outcome Assessment, Health Care; Proteinuria; Renin-Angiotensin System; Severity of Illness Index

Augmentation of intrarenal angiotensinogen (AGT) synthesis, secretion, and excretion is associated with the development of hypertension, renal oxidative stress, and tissue injury during ANG II-dependent hypertension. High salt (HS) exacerbates hypertension and kidney injury, but the mechanisms remain unclear. In this study, we determined the consequences of HS intake alone compared with chronic ANG II infusion and combined HS plus ANG II on the stimulation of urinary AGT (uAGT), renal oxidative stress, and renal injury markers. Sprague-Dawley rats were subjected to 1) a normal-salt diet [NS, n = 5]; 2) HS diet [8% NaCl, n = 5]; 3) ANG II infusion in NS rats [ANG II 80 ng/min, n = 5]; 4) ANG II infusion in HS rats [ANG II+HS, n = 5]; and 5) ANG II infusion in HS rats treated with ANG II type 1 receptor blocker (ARB) [ANG II+HS+ARB, n = 5] for 14 days. Rats fed a HS diet alone did not show changes in systolic blood pressure (SBP), proteinuria, cell proliferation, or uAGT excretion although they did exhibit mesangial expansion, collagen deposition, and had increased NADPH oxidase activity accompanied by increased peroxynitrite formation in the kidneys. Compared with ANG II rats, the combination of ANG II infusion and a HS diet led to exacerbation in SBP (175 ± 10 vs. 221 ± 8 mmHg; P < 0.05), proteinuria (46 ± 7 vs. 127 ± 7 mg/day; P < 0.05), and uAGT (1,109 ± 70 vs.. 7,200 ± 614 ng/day; P < 0.05) associated with greater collagen deposition, mesangial expansion, interstitial cell proliferation, and macrophage infiltration. In both ANG II groups, the O(2)(-) levels were increased due to increased NADPH oxidase activity without concomitant increases in peroxynitrite formation. The responses in ANG II rats were prevented or ameliorated by ARB treatment. The results indicate that HS independently stimulates ROS formation, which may synergize with the effect of ANG II to limit peroxynitrite formation, leading to exacerbation of uAGT and greater injury during ANG II salt hypertension.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Hypertension; Kidney; Male; NADPH Oxidases; Oxidative Stress; Peroxynitrous Acid; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Sodium Chloride, Dietary

The aim of this study was to evaluate the relationship of local intrarenal renin angiotensin system (RAS) with hypertension and proteinuria in renal transplant recipients. Sixty-nine nondiabetic renal transplant recipients (39 male, mean age: 36.3 ± 11.5 years) were included in this study. All patients were in stable condition with GFR greater than 30 ml/min/1.73 m(2); (MDRD). Hypertension was defined to be present if there was a recorded diagnosis of hypertension, systolic blood pressure >130 mmHg and/or diastolic blood pressure >80 mmHg according to ambulatory blood pressure monitoring. None of the hypertensive patients were receiving RAS blockers. Spot urine samples were obtained to measure urinary angiotensinogen (AGT) using human AGT-ELISA, urinary creatinine and protein levels. The demographic properties and laboratory findings were similar between hypertensive and normotensive transplant recipients. Urinary AGT-creatinine ratio (UAGT/UCre) was significantly higher in hypertensive patients compared with the normotensives (8.98 ± 6.89 μg/g vs. 5.48 ± 3.33 μg/g; P = 0.037). Importantly, a significantly positive correlation was found between UAGT/Ucre levels and proteinuria in hypertensive patients (P = 0.01, r = 0.405). Local intrarenal RAS probably plays an important role in the development of hypertension and proteinuria in renal transplant recipients.

Topics: Adult; Angiotensinogen; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Creatinine; Diastole; Enzyme-Linked Immunosorbent Assay; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney; Kidney Transplantation; Male; Middle Aged; Proteinuria; Renal Insufficiency; Systole

The aim of this study was to evaluate the relationship of local intrarenal renin angiotensin system (RAS) with proteinuria in patients with renal AA amyloidosis.. Thirty-two patients with renal AA amyloidosis (19 male, mean age: 45 ± 13 years) and sixteen healthy controls (5 male, mean age: 32 ± 5 years) were included in this study. Spot urine samples were obtained to measure urinary angiotensinogen (AGT) using human AGT-ELISA, urinary creatinine and protein levels. Logarithmic transformations of urinary AGT-creatinine ratio log(UAGT/Ucre) and urinary protein-to-creatinine ratio (UPCR) were done to obtain the normal distributions of these parameters.. Log(UAGT/UCre) was significantly higher in patients compared with the controls (1.88 ± 0.92 µg/g vs. 1.25 ± 0.70 µg/g; p = 0.023). Importantly a significantly positive correlation was found between log(UAGT/Ucre) and logUPCR in patients (r = 0.595, p = 0.006).. Urinary AGT levels are higher in renal AA amyloidosis patients than in controls. Also, there is a significant positive correlation between urinary AGT and proteinuria in renal AA amyloidosis.

Topics: Adult; Amyloidosis; Angiotensinogen; Biomarkers; Case-Control Studies; Creatinine; Familial Mediterranean Fever; Female; Humans; Kidney Diseases; Male; Middle Aged; Proteinuria; Regression Analysis; Serum Amyloid A Protein

Many chronic kidney disease (CKD) patients have persistent overt proteinuria despite angiotensin receptor blocker (ARB) treatment. This study investigated whether the initial difference in intrarenal renin-angiotensin system activity measured with urinary angiotensinogen would affect the antiproteinuric effects of ARB.. Between September 2005 and September 2008, in 50 non-diabetic proteinuric CKD patients not taking renin-angiotensin system inhibitors, the urinary protein/creatinine ratio (P/Cr), angiotensinogen/creatinine ratio (AGT/Cr), plasma renin and aldosterone were measured before starting valsartan, and were followed for 18 months.. Patients were divided into three groups according to their initial urinary AGT/Cr. The urinary P/Cr was lower in the low angiotensinogen group, but similar in the high and extremely high angiotensinogen groups (1.3±0.38 vs 2.0±0.92 vs 2.2±0.78). In all groups, the urinary P/Cr was decreased most for the first 6 months. The urinary P/Cr reduction at 6 months was greatest in the high angiotensinogen group (-24.2% vs -46.2% vs -16.4%). The urinary AGT/Cr was decreased most in the high angiotensinogen group. Renal functional deterioration was attenuated in the high angiotensinogen group compared with the extremely high angiotensinogen group.. The antiproteinuric effects of ARB were different according to the initial urinary angiotensinogen levels. These results suggest the potential value of the initial urinary AGT/Cr for predicting the therapeutic effect of ARB in proteinuric non-diabetic CKD patients.

Topics: Adolescent; Adult; Aged; Angiotensin Receptor Antagonists; Angiotensinogen; Female; Humans; Male; Middle Aged; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Treatment Outcome; Young Adult

The renoprotective effects of angiotensin receptor blockers vary considerably among individuals. We investigated the renoprotective effects of valsartan according to polymorphisms of the renin-angiotensin system and transforming growth factor-b1 (TGFB1) genes in patients with chronic non-diabetic proteinuric nephropathies.. Two hundred and thirty-nine non-diabetic patients with proteinuria of at least 1 g/day were enrolled. Patients received 80 g of valsartan daily, followed by 160 mg/day after 6 weeks. The follow-up period was 18 months. The status of the angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T, type 1 angiotensin II receptor (ATR1) A1166C, and TGFB1 C509 and T869C polymorphisms was determined in 162 patients.. Valsartan treatment caused a significant reduction in proteinuria from baseline throughout the study in patients with each genotype of the ACE, AGT and TGFB1 genes. However, patients with the ATR1 AC genotype had no significant reduction in proteinuria from baseline throughout the study course. The median reductions in proteinuria after 6 months were 45.7% and 10.8% in the patients with the ATR1 AA and AC genotypes, respectively (P = 0.034). The annual change in the estimated glomerular filtration rate did not differ significantly among the genotypes for each gene. On multiple regression analysis, the change in proteinuria after 6 months of treatment was independently associated with the ATR1 genotype and the change in blood pressure (P = 0.005 and 0.019, respectively).. Valsartan treatment significantly reduced the blood pressure and urinary protein excretion of patients with chronic non-diabetic proteinuric nephropathies. Interindividual differences in the anti-proteinuric effect of valsartan may be related partly to the ATR1 A1166C polymorphism.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Chronic Disease; Female; Genotype; Humans; Kidney; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prospective Studies; Protective Agents; Proteinuria; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta1; Valine; Valsartan

As a noninvasive examination, urinary proteomics is a very useful tool to identify renal disease. The purpose of the present study was to find differential proteins among women with preeclampsia, gestational hypertension and normal pregnancy, and to screen potential biomarkers for the early diagnosis of preeclampsia.. Urinary proteins were identified by iTRAQ labeling coupled with 2-D LC-MS/MS. The bioinformatics analysis was performed with the Metacore software and the International Protein Index (IPI) and the Gene Ontology (GO) Database. The differentially expressed proteins were verified by ELISA.. 362 nonredundant proteins were identified, 113 of which were expressed differentially between preeclampsia and normal pregnant group and 31 differential proteins among three groups. These differential proteins were associated with biological processes of blood coagulation, cell adhesion and differentiation, immune response and cytoskeleton development, etc. They interacted with each other in the network. The urinary angiotensinogen (AGT) was downregulated, which was consistent with the ELISA validation results.. The present study found a multitude of differential proteins that might provide a clue for investigating the mechanism of proteinuria development in preeclampsia. Low urinary angiotensinogen levels were useful for identifying preeclampsia.

Topics: Acute Kidney Injury; Adult; Angiotensinogen; Case-Control Studies; Chromatography, Liquid; Computational Biology; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Pregnancy; Proteinuria; Proteomics; Reproducibility of Results; Staining and Labeling; Tandem Mass Spectrometry

Chronic metabolic acidosis is a common metabolic disturbance and its clinical impact can be severe and extensive. The role and the change of the intrarenal renin-angiotensin system (RAS) during metabolic acidosis are uncertain, and whether acidosis can evoke inflammation remains unclear.. Male Sprague-Dawley rats were fed with water containing 0.14 M NH(4)Cl to induce metabolic acidosis for 1 and 8 weeks, respectively. They were compared with animals fed with deionized water (control) and equimolar sodium chloride water (NaCl). Gene expression analysis of RAS components included renin, renin/prorenin receptor, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II type 1 and 2 receptors (AT1R and AT2R). Histological examination was also performed to detect morphological change.. Acidosis was found in 1-week NH(4)Cl-treated rats but not in the 8-week group. More than twofold proteinuria and a significant decline of glomerular filtration rate (GFR) were observed in acid-loaded rats. Compared to the control and NaCl groups, angiotensinogen, ACE, AT1R and AT2R were significantly increased in the 1-week acidosis group (all p < 0.05). Sustained increase of AT1R expression was found as NH(4)Cl was continued for 8 weeks. There was no significant change in transforming growth factor-β and nuclear factor-κB. The architecture of tubular epithelial cells was affected during our experiment.. Metabolic acidosis induced proteinuria and decline of GFR in association with activation of intrarenal RAS.

Topics: Acidosis; Ammonium Chloride; Angiotensinogen; Animals; Gene Expression; Glomerular Filtration Rate; Male; NF-kappa B; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Time Factors; Transforming Growth Factor beta

The intrarenal renin-angiotensinogen system (RAS) plays a major role in the progression of chronic kidney disease. Urinary angiotensinogen (UAGT) provides a specific index of the intrarenal RAS status. This study was conducted to find the role of UAGT as a predictive marker in patients with immunoglobulin A nephropathy (IgAN).. Thirty-six patients with IgAN, 14 non-IgAN and 15 healthy controls were included. The UAGT concentration was measured using human ELISA kits and adjusted by urinary creatinine.. UAGT levels were significantly higher in patients with IgAN and non-IgAN than in healthy subjects (104.96 vs. 6.71 ng/mgCr, p < 0.01). Using univariate regression analysis, UAGT was found to correlate with the urine protein-to-creatinine ratio (UPCR), serum creatinine, and systolic and diastolic blood pressure in patients with IgAN. Multivariate regression analysis revealed that UAGT correlated positively with UPCR. Patients with levels of UAGT >100 ng/mgCr showed higher serum creatinine after treatment than patients with UAGT levels <100 ng/mgCr.. This study showed that UAGT levels are increased and correlate positively with the UPCR in IgAN. Patients with high levels of UAGT may have poor renal function following treatment.

Topics: Adult; Angiotensinogen; Biomarkers; Creatinine; Female; Glomerulonephritis; Glomerulonephritis, IGA; Humans; Male; Middle Aged; Proteinuria; Regression Analysis; Renin-Angiotensin System; Retrospective Studies

The intrarenal renin-angiotensin system (RAS) activation plays a pivotal role in immunoglobulin A nephropathy (IgAN) pathogenesis, which is still largely undefined. Recently, vasopressin (AVP) has been advocated to contribute to the genesis and progression of chronic kidney diseases (CKD) directly, and indirectly, via RAS activation. Our aim is to explore the intrarenal activity of AVP, its relationship with RAS activity, as well as its modulation by therapies in IgAN.. In this observational study, we measured plasma copeptin, a surrogate marker of AVP, the urine excretion of aquaporin 2 (AQP2), a protein reflecting renal AVP action, and angiotensinogen (AGT), a parameter of renal RAS activation, and their relationship with renal function in 44 IgAN patients at the time of renal biopsy, without any drug therapy, and after 6-month treatment with ACEi or steroid+ACEi. Twenty-one patients with other CKD and 40 healthy subjects were recruited as controls.. ELISAs were used to measure all variables of interest.. At baseline, IgAN patients showed higher urinary levels of AQP2, compared with controls and patients with other CKD. Urinary AQP2 and AGT levels strongly correlated with the presence of arterial hypertension. Steroids+ACEi caused the decrease of all the variables examined. The fall of urinary AQP2 and AGT following drug treatments was associated with the decrease of daily proteinuria.. Our findings would support the involvement of AVP-AQP2 axis, interacting with the RAS, in the progression of IgAN and candidate AQP2 as a possible novel marker of the disease.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Anti-Inflammatory Agents; Aquaporin 2; Arginine Vasopressin; Biomarkers; Bradykinin; Female; Glomerulonephritis, IGA; Glycopeptides; Humans; Hypertension, Renal; Logistic Models; Male; Middle Aged; Osmolar Concentration; Proteinuria; Renin-Angiotensin System; Steroids

In the present study, we hypothesized that HIV-1-induced occult HIV-associated nephropathy (HIVAN) would become apparent in the presence of adverse host factors. To test our hypothesis, Vpr mice (which display doxycycline-dependent Vpr expression in podocytes) with two, three, and four copies of the angiotensinogen (Agt) gene (Vpr-Agt-2, Vpr-Agt-3, and Vpr-Agt-4) were administered doxycycline for 3 weeks (to develop clinically occult HIVAN) followed by doxycycline-free water during the next 3 weeks. Subsequently, renal biomarkers were measured, and kidneys were harvested for renal histology. Vpr-Agt-2 developed neither proteinuria nor elevated blood pressure, and displayed minimal glomerular and tubular lesions only, without any microcyst formation. Vpr-Agt-3 showed mild glomerular and tubular lesions and microcyst formation, whereas Vpr-Agt-4 showed moderate proteinuria, hypertension, glomerular sclerosis, tubular dilation, microcysts, and expression of epithelial mesenchymal transition markers. Vpr-Agt-4 not only displayed enhanced renal tissue expression of Agt, renin, and angiotensin-converting enzyme, but also had higher renal tissue concentrations of angiotensin II. Moreover, renal cells in Vpr-Agt-4 showed enhanced expression of transforming growth factor-β, connective tissue growth factor, and vascular endothelial growth factor. These findings indicate that adverse host factors, such as the activation of the renin-angiotensin system, promote the progression of occult HIVAN to apparent HIVAN.

Topics: AIDS-Associated Nephropathy; Angiotensin II; Angiotensinogen; Animals; Biomarkers; Blood Pressure; Connective Tissue Growth Factor; Doxycycline; Epithelial-Mesenchymal Transition; Female; Gene Dosage; Genes, vpr; Host-Pathogen Interactions; Kidney; Male; Mice; Mice, Transgenic; Peptidyl-Dipeptidase A; Phenotype; Proteinuria; Renin; Renin-Angiotensin System; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

The Bogalusa Heart Study is a long-term study on cardiovascular disease and has followed a biracial (black/white) population from childhood. Risk factor data pertaining to many patients have been collected over 35 years, and the time course of hypertension has been documented by repeated examinations and measurements. Considerable sex and racial differences have been found to be related to cardiovascular disease. Urinary angiotensinogen (UAGT) is a novel biomarker for the intrarenal activity of the renin-angiotensin system in hypertension and kidney disease. We aimed to determine the relationship of UAGT with traditional cardiovascular disease risk factors in asymptomatic young adults in this biracial population.. We recruited 251 individuals and collected a single random spot urine sample from each one. Because UAGT is significantly increased in diabetic patients and the use of antihypertensive drugs affects UAGT levels, we excluded patients who had diabetes, who were receiving antihypertensive treatment, or both. Consequently, 190 participants were included for this analysis.. UAGT levels did not differ with race or sex, but were significantly correlated with SBP (r = +0.23, P = 0.0015) and DBP (r = +0.24, P = 0.0012). Moreover, high correlations were shown in men, especially in black men (SBP, r = +0.85, P = 0.0005 and DBP, r = +0.72, P = 0.0079). Thus, UAGT is correlated with blood pressure in men, even when they do not show overt proteinuria or albuminuria.. The biomarker, UAGT, may facilitate the identification of individuals that are at increased risk for the development of hypertension and early asymptomatic renal disease.

Topics: Adult; Albuminuria; Angiotensinogen; Black People; Blood Pressure; Cardiovascular Diseases; Humans; Hypertension; Hypotension; Kidney; Longitudinal Studies; Male; Proteinuria; Renin-Angiotensin System; Risk Factors; Urinary Tract; White People

The mRen(2).Lewis (mRen2) strain is an ANG II-dependent model of hypertension expressing marked sex differences in blood pressure and tissue injury that also exhibits estrogen and salt sensitivity. Because estrogen and salt influence angiotensinogen (AGT), circulating and renal expression of the protein were assessed in the mRen2 using a sensitive and specific ELISA. Hemizygous female and male mRen2 were placed on normal (1% NaCl, NS)- or high (8% NaCl, HS)-salt diets from 5 to 15 wk of age while a separate NS cohort was ovariectomized (OVX). The OVX mRen2 exhibited higher blood pressure (184 +/- 6 vs. 149 +/- 5 mmHg, n = 6), a 16-fold increase in urinary AGT (uAGT) (0.2 +/- 0.02 vs. 0.01 +/- 0.01 microg x kg(-1) x day(-1), P < 0.01), but no change in proteinuria (PROT). Excretion of AGT was correlated with blood pressure and PROT in the female groups. The HS diet led to higher blood pressure (224 +/- 8 mmHg), a 180-fold increase in uAGT (1.8 +/- 0.2 microg x kg(-1) x day(-1)), and increased PROT (98 +/- 9 vs. 7 +/- 1 mg x kg(-1) x day(-1)). Compared with females, NS males expressed higher excretion of uAGT (3.0 +/- 0.4 microg x kg(-1) x day(-1)) and PROT (32 +/- 5 mg x kg(-1) x day(-1)); both were increased eightfold with HS (uAGT: 23 +/- 3 microg x kg(-1) x day(-1); PROT: 285 +/- 28 mg x kg(-1) x day(-1)) without a change in blood pressure. Although uAGT was markedly higher in the OVX and HS groups, neither renal cortical AGT mRNA or protein expression was increased. Moreover, AGT release in cortical slices was similar for the NS and HS females. We conclude that the increase in uAGT with estrogen depletion or HS likely may be a biomarker for glomerular damage reflecting filtration of the circulating protein in the mRen2.

Topics: Angiotensinogen; Animals; Biomarkers; Blood Pressure; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Estrogens; Female; Hypertension; Kidney; Male; Mice; Ovariectomy; Proteinuria; Rats; Rats, Inbred Lew; Rats, Transgenic; Renin; RNA, Messenger; Sex Factors; Sodium Chloride, Dietary; Time Factors; Up-Regulation

The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, shows obesity, hyperglycemia, and hyperlipidemia from 6 weeks of age. Diabetic complications such as nephropathy and cataract are observed with aging; however, blood pressure change with age has not previously been examined. In this study, blood pressure was periodically measured and the change was investigated. Blood pressure in male SDT-fa/fa rats was elevated at 8, 16, and 24 weeks of age, whereas the heart rate was not changed. In addition to hyperglycemia, hyperlipidemia, and proteinuria, hyperleptinemia and increased urine angiotensinogen were observed in SDT-fa/fa rats. Blood pressure and heart rate in the male original SDT (SDT-+/+) rat did not significantly change. In conclusion, the SDT-fa/fa rat is a promising model, showing significant hypertension with diabetes mellitus.

Topics: Angiotensinogen; Animals; Blood Pressure; Diabetes Mellitus, Type 2; Disease Models, Animal; Heart Rate; Hyperglycemia; Hyperlipidemias; Hypertension; Leptin; Male; Obesity; Proteinuria; Rats; Rats, Sprague-Dawley

Preeclampsia is the major cause of maternal and fetal mortality/morbidity. Because hypertension is an important risk factor for preeclampsia, we investigated whether hypertensive mice that overexpress human renin and angiotensinogen develop superimposed preeclampsia. Given that the mechanisms underlying this disease are still poorly understood, animal models are of great use for elucidation. Blood pressure and proteinuria were measured by telemetry and ELISA, respectively. Heart function was evaluated by echocardiography, whereas pathological cardiac hypertrophy-related genes were assessed by real-time PCR. Soluble fms-like tyrosine kinase 1 plasma concentrations were quantitated by ELISA and placental expression by real-time PCR. Transgenic mice develop de novo proteinuria during gestation and marked blood pressure elevation, which are hallmarks of superimposed preeclampsia on chronic hypertension. Abnormal placentation present in these mothers produced a significant decrease in pup and placental weight and was associated with an increased placental expression of soluble fms-like tyrosine kinase 1. We also found heightened circulating levels of this receptor, when adjusted for placental mass, as has been observed in women who suffer from preeclampsia. Cardiac hypertrophy could be observed in the transgenic mice and was exacerbated by gestation. As a result, heart function was significantly decreased, and markers of pathological hypertrophy were increased. Our data, thus, confirm the characterization of a new model of superimposed preeclampsia on chronic hypertension. Because chronically hypertensive women are at risk of developing the pathology, our model reflects a clinical reality and is, thus, an excellent tool to elucidate the molecular mechanisms triggering this disease.

Topics: Angiotensinogen; Animals; Animals, Newborn; Blood Pressure; Cardiomegaly; Chronic Disease; Disease Models, Animal; Female; Humans; Hypertension; Mice; Mice, Inbred C57BL; Mice, Transgenic; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Renin; Renin-Angiotensin System

The differential roles of circulating and intrarenal renin-angiotensin system (RAS) in glomerulonephritis have not been elucidated. In this study, we investigated the levels of circulating and intrarenal RAS activity and urinary angiotensinogen (AGT) excretion in anti-thymocyte serum (ATS) nephritis induced by an ATS injection (ATS group). The effect of olmesartan, an angiotensin II (ANG II) type 1 receptor blocker (ARB), on the development of nephritis was also examined (ATS+ARB group). In addition, the rats received a saline injection instead of ATS (control group). Mesangial proliferation with transient proteinuria, which peaked at day 7, was significantly increased in the ATS group compared with the control group. The levels of glomerular AGT mRNA, intrarenal ANG II, and urinary AGT excretion in the ATS group were increased significantly at day 7 compared with the control group. Administration of olmesartan (ATS+ARB group) significantly decreased the levels of renal lesions, proteinuria, and intrarenal RAS activity compared with the ATS group. In addition, the levels of urinary AGT excretion correlated with the levels of glomerular damage, urinary protein excretion, and immunoreactivity for AGT and ANG II in kidney. On the other hand, plasma renin activity was significantly lower in the ATS group compared with the control group and significantly higher in the ATS+ARB group than in the ATS group. These data suggest that an increase in kidney-specific RAS activity, which parallels urinary AGT excretion, plays an important role in the development of ATS nephritis.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Antilymphocyte Serum; Blood Pressure; Gene Expression; Glomerulonephritis, Membranoproliferative; Imidazoles; Kidney; Male; Proteinuria; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; RNA, Messenger; Tetrazoles

There are two major pathophysiologic processes involved in the development of hypertension: (1) expanded extracellular fluid volume and (2) vasoconstriction. We have developed a model of preeclampsia in the rat, in which excessive volume expansion (VE) plays a role. These animals excrete increased amounts of the bufodienolide, marinobufagenin (MBG), even before their hypertension and proteinuria become established. Furthermore, their hypertension is corrected by administration of resibufogenin (RBG), a compound structurally similar to MBG.. We studied two models of experimental hypertension in the nonpregnant animal, produced either by deoxycorticosterone acetate (DOCA)-salt administration or by angiotensin infusion.. RBG administered to the DOCA-salt rats lowered blood pressure and reduced proteinuria in the VE animals, but had no affect on the rats infused with angiotensin. Furthermore, although the production of superoxide anion in the aortas of both groups of hypertensive rats was increased over control, RBG reduced these levels to normal in the VE (DOCA-salt) animals only. RBG had no effect in the angiotensin-infused rats. The urinary excretion of angiotensinogen did not rise in VE-mediated hypertension, but did increase in the angiotensin-infused rats.. MBG plays an important role in the causation of hypertension in the VE rats, but not in the vasoconstrictive model. RBG is effective only in VE-mediated hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Bufanolides; Creatinine; Desoxycorticosterone; Disease Models, Animal; Hypertension, Renal; Male; Mineralocorticoids; Proteinuria; Rats; Rats, Inbred Strains; Sodium Chloride; Superoxides; Vasoconstrictor Agents

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

This study was performed to determine whether immunoreactivity of intrarenal hemeoxygenase-1 and angiotensinogen are increased in IgA nephropathy (IgAN) patients. Hemeoxygenase-1 and angiotensinogen immunoreactivity were determined by immunohistochemistry robot system in renal specimens from 39 patients with IgAN. Normal portions of surgically resected kidney served as controls. IgAN patients showed moderate proteinuria (1.1+/-0.2 g/day); however, the control group did not show any proteinuria. Immunoreactivity of intrarenal hemeoxygenase-1 and angiotensinogen in IgAN were significantly increased compared to normal kidneys (2.42+/-0.42 vs 1.00+/-0.26 for hemeoxygenase-1 and 4.05+/-0.40 vs 1.00+/-0.21 for angiotensinogen, arbitrary unit). Even though these IgAN patients did not show massive renal damage, hemeoxygenase-1 and angiotensinogen immunoreactivity were increased in these patients at this time point. These data suggest that activated intrarenal reactive oxygen species-angiotensinogen axis plays some roles in development of IgAN at the early stage and will provide supportive foundation of effectiveness of the renin-angiotensin system blockade in IgAN.

Topics: Adult; Angiotensinogen; Female; Glomerulonephritis, IGA; Heme Oxygenase-1; Humans; Kidney; Male; Middle Aged; Oxidative Stress; Proteinuria; Reactive Oxygen Species

To test the hypothesis that genetically determined alterations of the renin-angiotensin system are associated with hypertensive disorders in pregnancy.. A genetic association study was conducted at the obstetrics department of the Charité university hospital, Berlin, Germany. A total of 1068 Caucasian women were consecutively included after delivery and genotyped for the angiotensinogen M235T polymorphism and the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism.. Women homozygous for the angiotensinogen T allele have significantly elevated mean systolic and diastolic blood pressures in the third trimester (118.4 +/- 1.1/71.5 +/- 0.7 versus 116.9 +/- 0.3/70.4 +/- 0.2 mmHg, n = 128 versus 940; P < 0.05). This finding is especially pronounced in the subgroup of primigravid women. The ACE polymorphism is not associated with blood pressure during pregnancy. None of the polymorphisms is associated with urinary protein excretion or oedema during pregnancy. Maternal polymorphisms do not influence fetal growth and birth weight. There is, however, an interesting trend towards an increased incidence of circulatory system malformations in newborns carrying alleles that are known to be associated with decreased intrinsic renin-angiotensin system activity.. We demonstrate for the first time in a large Caucasian population that a common maternal polymorphism of the angiotensinogen gene is related to a blood pressure increase during pregnancy. The angiotensinogen M235T polymorphism might contribute to the multifactorial pathogenesis of gestational hypertension and pre-eclampsia.

Topics: Amino Acid Substitution; Angiotensinogen; Blood Pressure; Case-Control Studies; DNA Transposable Elements; Female; Humans; Hypertension; Infant, Newborn; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Proteinuria; Sequence Deletion

The clinical course of Henoch-Schönlein Purpura (HSP) in children is variable, with some patients having a much more rapidly progressing course than others. We investigated whether polymorphisms of the renin-angiotensin system (RAS) genes are involved in HSP. Three RAS genotypes were examined in 114 children with HSP and in 164 healthy children: the angiotensin I converting enzyme (ACE) insertion/deletion polymorphism, the M235T mutation in the angiotensinogen gene (Agt), and the A1166C in the angiotensin II type I receptor (AT1R) gene. Significant differences were observed between HSP patients and control group in the frequency of ACE and Agt genotypes (p=0.004 and p=0.003, respectively). The TT genotype of Agt gene was associated with a 3.5-fold increased risk for Henoch-Schönlein nephritis (HSN) compared with the MM/MT genotype (odds ratio, 3.5; 95% confidence interval, 1.2-10.4). There was a trend to a higher prevalence of the TT genotype of the Agt gene among patients with nephrotic range proteinuria when compared to the patients with mild proteinuria, although the difference did not reach a statistical significance. The results of this study suggest that polymorphisms of ACE gene and Agt gene likely influence the risk of developing HSP. However, among the three genes of the RAS studies, only Agt gene was associated with the susceptibility to HSN. RAS gene polymorphisms studied are not associated with the presence of nephrotic range proteinuria. Additional studies are warranted to verify the correlation between RAS gene polymorphisms and susceptibility to HSP.

Topics: Adolescent; Alanine; Angiotensinogen; Child; Child, Preschool; Cysteine; DNA Transposable Elements; Female; Gene Deletion; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; IgA Vasculitis; Kidney Diseases; Male; Methionine; Nephrotic Syndrome; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Proteinuria; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Severity of Illness Index; Threonine

Angiotensinogen (ANG) is the sole substrate of the renin-angiotensin system (RAS). Clinical studies have shown that RAS activation may lead to hypertension, a major cardiovascular and renal risk factor. To delineate the underlying mechanisms of hypertension-induced nephropathy, we generated transgenic mice that overexpress rat ANG (rANG) in the kidney to establish whether intrarenal RAS activation alone can evoke hypertension and kidney damage and whether RAS blockade can reverse these effects. Transgenic mice overexpressing renal rANG were generated by employing the kidney-specific, androgen-regulated protein promoter linked to rANG cDNA. This promoter targets rANG cDNA to renal proximal tubules and responds to androgen stimulation. Transgenic mice displayed kidney-specific expression of rANG, significantly increased blood pressure (BP) and albuminuria in comparison to non-transgenic littermates. Administration of losartan (an angiotensin II (type 1)-receptor antagonist) or perindopril (an angiotensin-converting enzyme inhibitor) reversed these abnormalities in transgenic animals. Renal injury was evident on examination of the kidneys in transgenic mice, and attenuated by losartan and perindopril treatment. We conclude that the overproduction of ANG alone in the kidney induces an increase in systemic BP, proteinuria, and renal injury. RAS blockers prevent these abnormalities. These data support the role of the intrarenal RAS in the development of hypertension and renal injury.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Blotting, Western; DNA, Complementary; Female; Gene Expression Regulation; Hypertension; Immunohistochemistry; Kidney; Kidney Diseases; Losartan; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Perindopril; Proteins; Proteinuria; Rats; Renin-Angiotensin System

This study was performed to test the significance of urinary angiotensinogen (UAGT) in essential hypertensive patients stratified as a function of plasma renin and aldosterone.. A sample of 248 essential hypertensives, investigated under their usual sodium diet and either off-medication or under a standardized treatment, was separated into two groups on the basis of upright plasma active renin and aldosterone medians. Patients with plasma active renin and aldosterone below medians are referred to as the low renin-aldosterone essential hypertensive group (LRA-EH). Others subjects are defined as other essential hypertensives (O-EH). Blood pressure (BP) was recorded by 24-h ambulatory monitoring. UAGT was measured by a specific enzyme-linked immunosorbent assay for total angiotensinogen. Because UAGT was markedly increased in the presence of overt proteinuria (>/= 300 mg/24 h), proteinuric patients (n = 29) were excluded from subsequent analyses. UAGT was a significant predictor of systolic and diastolic BP in LRA-EH females (P < 0.01 and P = 0.05, respectively) but not in males. By contrast, urinary sodium excretion (P < 0.001) and maintenance of treatment (P = 0.002) were significant predictors of systolic BP in males. These correlations were not observed in O-EH, whether males or females.. In the present study, UAGT stands as a strong predictor of BP in women with low plasma renin/aldosterone, suggesting an involvement of the tubular renin-angiotensin system in these subjects. Higher sodium intake or the need to maintain treatment may account in part for the lack of a similar relationship in males.

Topics: Aged; Aldosterone; Angiotensinogen; Blood Pressure; Female; Humans; Hypertension, Renal; Male; Middle Aged; Predictive Value of Tests; Proteinuria; Renin; Renin-Angiotensin System; Sex Factors

Intrarenal activation of the renin-angiotensin system has been suggested to play a pivotal role in the progression of various renal diseases, but the regulation of each component has not been fully clarified. We investigated the roles of nuclear factor kappaB (NF-kappaB) activation in the intrarenal renin-angiotensin system changes induced by proteinuria.. We used unilaterally nephrectomized rats loaded with bovine serum albumin as a model of proteinuric renal injury. Renal NF-kappaB activation was inhibited by gene transfer of the truncated form of IkappaBalpha via injection of a recombinant adenovirus vector into the renal artery, as we reported previously.. Inhibition of renal NF-kappaB activation attenuated the increases in intrarenal angiotensinogen protein (2.0-fold in rats with protein overloading and saline injection to 1.3-fold in rats with protein overloading and injection of a truncated form of IkappaBalpha) and angiotensin II (1.8-fold to 1.2-fold), and angiotensinogen mRNA. The increases in angiotensin-converting enzyme (ACE) and angiotensin II receptor type 2 were unaffected by NF-kappaB inhibition. The expression of ACE2, an enzyme that metabolizes angiotensins I and II, was decreased by 37%, and NF-kappaB inhibition abolished the decrease. Immunohistochemical analysis revealed that the angiotensinogen and ACE2 expression changes occurred mainly in proximal tubule cells (i.e., the target of adenoviral gene transfer).. These results indicate that proteinuria induces an increase in renal angiotensin II in an NF-kappaB-dependent manner. Induction of angiotensinogen and decrease in ACE2 levels may be involved in this NF-kappaB-dependent increase in angiotensin II.

Topics: Adenoviridae; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Carboxypeptidases; Dietary Proteins; Female; I-kappa B Proteins; Kidney; NF-kappa B; NF-KappaB Inhibitor alpha; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; RNA, Messenger

We have previously reported that the TT genotype of the angiotensinogen gene and the ID/DD genotype of the angiotensin-converting enzyme gene are associated with increased severity of proteinuria in IgA nephropathy in Japanese children. Recently it was reported that polymorphism at -20 from adenine to cytosine in the angiotensinogen gene, increasing the level of this transcript, was associated with the progression of renal dysfunction in adult IgA nephropathy. We therefore investigated whether this polymorphism is involved in IgA nephropathy in Japanese children. We identified this polymorphism in 105 children with IgA nephropathy and 119 healthy adults using polymerase chain reaction/restriction fragment length polymorphism analysis. At the time of biopsy, all patients had normal blood pressure and renal function. There were no differences in the genotypes and allele frequencies of this polymorphism between patients with IgA nephropathy and controls. The number of patients with the AC/CC genotype showing heavy proteinuria (>or=1.0 g/day per m(2) body surface area) at biopsy was significantly higher than that with the AA genotype ( P=0.039, chi-squared test). The AC/CC genotype of this polymorphism may be associated with an increased severity of proteinuria, suggesting that this polymorphism may play a significant role in the progression of IgA nephropathy in Japanese children.

Topics: Adenine; Adolescent; Angiotensinogen; Asian People; Case-Control Studies; Child; Cytosine; Female; Genotype; Glomerulonephritis, IGA; Humans; Male; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Proteinuria

Angiotensin (Ang) II-infused hypertensive rats exhibit increases in renal angiotensinogen mRNA and protein, as well as urinary angiotensinogen excretion in association with increased intrarenal Ang II content. The present study was performed to determine if the augmentation of intrarenal angiotensinogen requires activation of Ang II type 1 (AT1) receptors. Male Sprague-Dawley rats (200 to 220 g) were divided into 3 groups: sham surgery (n=10), subcutaneous infusion of Ang II (80 ng/min, n=11), and Ang II infusion plus AT1 blocker (ARB), olmesartan (5 mg/d, n=12). Ang II infusion progressively increased systolic blood pressure (SBP) compared with sham (178+/-8 mm Hg versus 119+/-4 at day 11). ARB treatment prevented hypertension (113+/-6 at day 11). Twenty-four-hour urine collections were taken at day 12, and plasma and tissue samples were harvested at day 13. The Ang II+ARB group had a significant increase in plasma Ang II compared with Ang II and sham groups (365+/-46 fmol/mL versus 76+/-9 and 45+/-14, respectively). Nevertheless, ARB treatment markedly limited the enhancement of kidney Ang II by Ang II infusion (65+/-17 fmol/g in sham, 606+/-147 in Ang II group, and 288+/-28 in Ang II+ARB group). Ang II infusion significantly increased kidney angiotensinogen compared with sham (1.69+/-0.21 densitometric units versus 1.00+/-0.17). This change was reflected by increased angiotensinogen immunostaining in proximal tubules. ARB treatment prevented this increase (1.14+/-0.12). Urinary angiotensinogen excretion rates were enhanced 4.7x in Ang II group (4.67+/-0.41 densitometric units versus 1.00+/-0.21) but ARB treatment prevented the augmentation of urinary angiotensinogen (0.96+/-0.23). These data demonstrate that augmentation of intrarenal angiotensinogen in Ang II-infused rats is AT1-dependent and provide further evidence that urinary angiotensinogen is closely linked to intrarenal Ang II in Ang II-dependent hypertension.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Hypertension; Imidazoles; Kidney; Kidney Tubules, Proximal; Male; Olmesartan Medoxomil; Proteinuria; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin; Tetrazoles

This study was performed to examine whether there is an inappropriate regulation of intrarenal angiotensinogen in Dahl-salt sensitive rats (DS) fed a high salt diet (HS). Dahl salt-resistant rats (DR) and DS were maintained on HS (8% NaCl) or low salt diet (LS, 0.3% NaCl) for 4 weeks. Systolic blood pressure (SBP), measured by tail-cuff plethysmography, was unaltered in DR (DR+HS, 127+/-3 mm Hg, n=5; DR+LS, 126+/-3, n=5); however, SBP was significantly increased in DS+HS (208+/-7, n=9) compared with DS+LS (134+/-2, n=5). HS suppressed plasma renin activity in both strains (0.7+/-0.2 ng of angiotensin I/mL per hour in DS+HS, 3.1+/-0.5 in DS+LS, 0.8+/-0.2 in DR+HS, 5.1+/-0.7 in DR+LS). Plasma angiotensinogen levels, measured by Western blot analysis, were also suppressed by HS in both strains (36 919+/-2170 integrated densitometric unit in DS+HS, 53 028+/-2752 in DS+LS, 44 722+/-1721 in DR+HS, 55782+/-3785 in DR+LS). However, kidney angiotensinogen levels were significantly increased in DS+HS (75 850+/-4171, integrated densitometric unit) compared with DS+LS (47 232+/-3470), DR+HS (44 748+/-8236), and DR+LS (42 504+/-4052). Urinary excretion of angiotensinogen, measured by radioimmunoassay of angiotensin I after incubation with excess renin, had a similar profile. Urinary excretion of angiotensinogen was significantly increased in DS+HS (2958+/-531 pmol/d) compared with DS+LS (56+/-4), DR+HS (31+/-12), and DR+LS (21+/-7). These data indicate that intrarenal angiotensinogen is enhanced in DS+HS, which is reflected by the increased urinary excretion of angiotensinogen. The results suggest that DS on HS have an inappropriate augmentation of intrarenal angiotensinogen, which may contribute to impaired sodium excretion during a high salt diet and the development of hypertension in this strain.

Topics: Angiotensinogen; Animals; Blood Pressure; Blotting, Western; Hypertension; Kidney; Kinetics; Male; Proteinuria; Rats; Rats, Inbred Dahl; Renin; Sodium Chloride; Urine

The regulation of blood pressure during pregnancy involves several biological pathways. Candidate genes implicated in hypertensive diseases during pregnancy include those of the renin-angiotensin system and nitric oxide synthase (NOS). We evaluated blood pressure and metabolic characteristics during pregnancy in mutant mice. These included mice with a null mutation in the endothelial NOS (eNOS) gene (Nos3(-/-)), four copies of the angiotensinogen gene (Agt(2/2)), and mutations in both genes [four copies of Agt and heterozygous deficient for eNOS (Agt(2/2)Nos3(+/-)), four copies of Agt and homozygous deficient for eNOS (Agt(2/2)Nos3(-/-))]. Blood pressure measurements of nulliparous females from mutant strains were compared with two common laboratory strains C57Bl6/J and SV129 throughout their first pregnancy. Serum and urine analysis for the evaluation of renal and liver physiology were measured in the prepregnant state and during the third trimester of pregnancy. Throughout pregnancy blood pressures in all mutant strains were higher compared with controls. Agt(2/2)Nos3(-/-) showed the highest blood pressures and C57Bl6/J the lowest. Control mice, but not mutant mice, showed a second trimester decline in blood pressure. No immediate differences were noted regarding behavioral characteristics, renal or liver function parameters. Mice deficient for eNOS, mice with overexpression of Agt, and mice with mutations in both genes demonstrated higher blood pressure throughout pregnancy. There was no evidence of renal dysfunction, liver dysfunction, or hemolysis among any of the strains studied. We conclude that Nos3 and Agt are important genes in the regulation of blood pressure during pregnancy.

Topics: Angiotensinogen; Animals; Area Under Curve; Behavior, Animal; Blood Pressure; Breeding; Disease Models, Animal; Energy Metabolism; Female; Gene Expression Regulation, Enzymologic; Genotype; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pre-Eclampsia; Pregnancy; Proteinuria

We investigated whether polymorphisms of the renin-angiotensin system genes are involved in IgA nephropathy in Japanese children. We identified the M235T polymorphism of the angiotensinogen (AGT) gene, the I/D polymorphisms of the angiotensin-converting enzyme (ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor gene in 95 Japanese children with IgA nephropathy and 99 healthy Japanese adults. There were no differences in the genotype and allele frequencies of these genes between patients with IgA nephropathy and controls. Urinary protein excretion at the time of biopsy was significantly greater in patients with the TT genotype of the AGT gene than in those with the MM/MT genotypes of the AGT gene (1.32 +/- 1.42 versus 0.75 +/- 0.78 g/day; P = 0.01) and in patients with the ID/DD genotypes of the ACE gene than in those with the II genotype of the ACE gene (1.45 +/- 1.50 versus 0.63 +/- 0.56 g/day; P = 0.001). Thus, the TT genotype of the AGT gene and the ID/DD genotype of the ACE gene are associated with increased severity of proteinuria, suggesting that AGT and ACE gene polymorphisms may play a significant role in the progression of IgA nephropathy in Japanese children.

Topics: Adolescent; Alleles; Angiotensinogen; Child; Female; Gene Frequency; Genotype; Glomerulonephritis, IGA; Humans; Kidney; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Proteinuria; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System

Genetic variability in the renin-angiotensin system may modify renal responses to injury and disease progression. We examined whether the M235T polymorphism of the angiotensinogen (AGT) gene, the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene, and the A1166--> C polymorphism of the angiotensin II type 1 receptor gene may be associated with disease progression in 168 Caucasian patients with IgA nephropathy. All patients had serial measurements of their creatinine clearance, proteinuria, and blood pressure (mean+/-SD) with a follow-up of 6.1+/-4.7 yr. The genotype frequencies for each gene were consistent with Hardy-Weinberg equilibrium, and were similar to those of 100 Caucasian control subjects. We examined two primary outcomes: (a) the rate of deterioration of Ccr, and (b) the maximal level of proteinuria. We found that patients with the AGT MT (n = 79) and TT (n = 29) genotypes had a faster rate of deterioration of Ccr than those with the MM (n = 60) genotype (i.e., median values, -6.6 and -6.2 vs. -3. 0 ml/min/yr, respectively; P = 0.01 by Kruskal-Wallis test). Similarly, patients with AGT MT and TT genotypes had higher maximal values of proteinuria than those with the MM genotype (i.e., median values, 2.5 and 3.5 vs. 2.0 g/d, respectively; P < 0.02 by Kruskal-Wallis test). Neither the ACE insertion/deletion nor angiotensin II type I A1166--> C gene polymorphism was associated with disease progression or proteinuria in univariate analysis. Multivariant analysis, however, detected an interaction between the AGT and ACE gene polymorphisms with the presence of ACE/DD polymorphism adversely affecting disease progression only in patients with the AGT/MM genotype (P = 0.008). Neither of these gene polymorphisms was associated with systemic hypertension. Our results suggest that polymorphisms at the AGT and ACE gene loci are important markers for predicting progression to chronic renal failure in Caucasian patients with IgA nephropathy.

Topics: Adult; Aged; Angiotensinogen; Blood Pressure; Creatinine; Disease Progression; Female; Genotype; Glomerulonephritis, IGA; Humans; Kidney Function Tests; Male; Middle Aged; Multivariate Analysis; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Proteinuria; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Risk Factors; White People

Topics: Alleles; Angiotensinogen; Base Sequence; Female; Genetic Predisposition to Disease; Humans; Iceland; Molecular Sequence Data; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy; Prospective Studies; Proteinuria; Repetitive Sequences, Nucleic Acid; Scotland