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Preeclampsia (preE) is a hypertensive disorder in pregnancies. It is the third leading cause of mortality among pregnant women and fetuses worldwide, and there is much we have yet to learn about its pathophysiology. One complication includes cerebral edema, which causes a breach of the blood–brain barrier (BBB). Urinary marinobufagenin (MBG) is elevated in a preE rat model prior to developing hypertension and proteinuria. We investigated what effect MBG has on the endothelial cell permeability of the BBB. Human brain microvascular endothelial cells (HBMECs) were utilized to examine the permeability caused by MBG. The phosphorylation of ERK1/2, Jnk, p38, and Src was evaluated after the treatment with MBG. Apoptosis was evaluated by examining caspase 3/7. MBG ≥ 1 nM inhibited the proliferation of HBMECs by 46–50%. MBG induced monolayer permeability, causing a decrease in the phosphorylation of ERK1/2 and the activated phosphorylation of Jnk, p38, and Src. MBG increased the caspase 3/7 expression, indicating the activation of apoptosis. Apoptotic signaling or the disruption of endothelia tight junction proteins was not observed when using the p38 inhibitor as a pretreatment in MBG-treated cells. The MBG-induced enhancement of the HBMEC monolayer permeability occurs by the downregulation of ERK1/2, the activation of Jnk, p38, Src, and apoptosis, resulting in the cleavage of tight junction proteins, and are attenuated by p38 inhibition. [ABSTRACT FROM AUTHOR]

Every year millions die prematurely of complications related to chronic kidney disease (CKD). Main causes of death are connected with cardiovascular (CV) complications. There is no cure for CKD although current treatment can slow the progression of the disease if diagnosed early. Fortunately, last decades have witnessed an accelerating pace of discovery regarding the cellular and molecular basis for CKD and CV disease. Novel biomarkers, including amino-terminal type III procollagen peptide (PIIINP), carboxy-terminal type I procollagen peptide (PICP), FGF23, marinobufagenin, and several miRNAs, show promise for early detection and risk stratification. In this review, we provide an overview of recent advances in the "fibrotic concept" of the etiology and pathogenesis of CKD which involves system consisting of Na/K-ATPase and its endogenous ligands including marinobufagenin which inhibits Fli1 and stimulates synthesis of collagen-1 in the vasculature. A novel treatment of CKD already involves the use of mineralocorticoid receptor antagonists capable of impairing marinobufagenin-Na/K-ATPase interactions. [ABSTRACT FROM AUTHOR]

Marinobufagenin (MBG) is implicated in chronic kidney disease, where it removes Fli1-induced inhibition of the collagen-1. We hypothesized that (i) in nephrectomized rats, aortic fibrosis develops due to elevated plasma MBG and inhibited Fli1, and (ii) that the antibody to MBG reduces collagen-1 and improves vasodilatation. A partial nephrectomy was performed in male Sprague-Dawley rats. Sham-operated animals comprised the control group. At 5 weeks following nephrectomy, rats were administered the vehicle (n = 8), or the anti-MBG antibody (n = 8). Isolated aortic rings were tested for their responsiveness to sodium nitroprusside following endothelin-1-induced constriction. In nephrectomized rats, there was an increase in the intensity of collagen staining in the aortic wall vs. the controls. In antibody-treated rats, the structure of bundles of collagen fibers had ordered organization. Western blots of the aorta had lower levels of Fli1 (arbitrary units, 1 ± 0.05 vs. 0.2 ± 0.01; p < 0.001) and greater collagen-1 (arbitrary units, 1 ± 0.01 vs. 9 ± 0.4; p < 0.001) vs. the control group. Administration of the MBG antibody to rats reversed the effect of the nephrectomy on Fli1 and collagen-1 proteins. Aortic rings pretreated with endothelin-1 exhibited 50% relaxation following the addition of sodium nitroprusside (EC50 = 0.28 μmol/L). The responsiveness of the aortic rings obtained from nephrectomized rats was markedly reduced (EC50 = 3.5 mol/L) compared to the control rings. Treatment of rats with the antibody restored vasorelaxation. Thus, the anti-MBG antibody counteracts the Fli1-collagen-1 system and reduces aortic fibrosis. [ABSTRACT FROM AUTHOR]

Leptin has important roles in numerous physiological functions, including those in the regulation of energy balance, and in immune and reproductive systems. However, in the recent years, evidence has implicated it in a number of obesity-related diseases, where its concentrations in serum are significantly elevated. Elevated serum leptin concentrations and increased placental leptin secretion have been reported in women with hypertensive disorders of pregnancy. Whether leptin is responsible for this disorder remains to be established. Leptin injections in healthy rats and mice during pregnancy result in endothelial activation, increased blood pressure and proteinuria. A potential role for leptin in the pathogenesis of pre-eclampsia is hypothesised, particularly in women who are overweight or obese where serum leptin concentrations are often elevated. This review summarises pertinent information in the literature on the role of leptin in puberty, pregnancy, and hypertensive disorders of pregnancy. In particular, the possible mechanism that may be involved in leptin-induced increase in blood pressure and proteinuria during pregnancy and the potential role of marinobufagenin in this disease entity. We hypothesise a significant role for oxidative stress in this, and propose a conceptual framework on the events that lead to endothelial activation, raised blood pressure and proteinuria following leptin administration. Leptin is necessary for normal pubertal development and pregnancy; however, raised concentrations of leptin may have serious adverse effects on pregnancy. This review summarises pertinent information in the literature on the role of leptin in puberty, pregnancy and, pregnancy hypertension. Evidence suggests a significant role for oxidative stress in this, and propose a conceptual framework on the possible events that lead to endothelial activation, raised blood pressure and proteinuria following leptin administration. Image by Harbindarjeet Singh and Fayez Almabhouh. [ABSTRACT FROM AUTHOR]

Background and Objectives: Acute kidney injury (AKI) remains a significant complication following major cardiac surgery. Marinobufagenin (MBG), a cardiotonic steroid involved in sodium balance and blood pressure regulation, has been linked to organ damage after ischemia–reperfusion events. This pilot, prospective study investigates the utility of circulating MBG to improve AKI risk assessment in cardiac surgery patients as a stand-alone biomarker and after inclusion in a validated risk model (STS-AKI score). Materials and Methods: We included 45 patients undergoing elective cardiac surgery. The MBG levels were measured preoperatively and at 4, 8, and 12 h post-surgery. The AKI was defined according to the KDIGO guidelines. Statistical analyses assessed the diagnostic and prognostic utility of MBG and its integration with the STS-AKI score. Results: An AKI occurred in 26.7% of the patients. The STS-AKI score performed well in this cohort (AUC: 0.736). The MBG levels displayed a decreasing trend in the whole population after surgery (p = 0.02). However, in the AKI patients, MBG increased at 4 and 8 h before decreasing at 12 h post-surgery. The MBG changes from the baseline to 8 h and from 8 to 12 h post-surgery showed a remarkable diagnostic accuracy for an AKI (AUCs: 0.917 and 0.843, respectively). Integrating these MBG changes with the STS-AKI score significantly improved the model performance, including discrimination, calibration, and risk reclassification. Conclusions: The MBG measurement, particularly any dynamic changes post-surgery, enhances AKI risk stratification in cardiac surgery patients. Integrating MBG with the STS-AKI score offers more accurate risk predictions, potentially leading to better patient management and outcomes. [ABSTRACT FROM AUTHOR]

Every year millions die prematurely of complications related to chronic kidney disease (CKD). Main causes of death are connected with cardiovascular (CV) complications. There is no cure for CKD although current treatment can slow the progression of the disease if diagnosed early. Fortunately, last decades have witnessed an accelerating pace of discovery regarding the cellular and molecular basis for CKD and CV disease. Novel biomarkers, including amino-terminal type III procollagen peptide (PIIINP), carboxy-terminal type I procollagen peptide (PICP), FGF23, marinobufagenin, and several miRNAs, show promise for early detection and risk stratification. In this review, we provide an overview of recent advances in the “fibrotic concept” of the etiology and pathogenesis of CKD which involves system consisting of Na/K-ATPase and its endogenous ligands including marinobufagenin which inhibits Fli1 and stimulates synthesis of collagen-1 in the vasculature. A novel treatment of CKD already involves the use of mineralocorticoid receptor antagonists capable of impairing marinobufagenin-Na/K-ATPase interactions.

Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950s and 1960s, we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na+/Ca2+ exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, subnanomolar ouabain sometimes stimulates NKA while higher concentrations are invariably inhibitory. Second, endogenous ouabain (EO) was discovered in the human circulation. Third, in the DIG clinical trial, digoxin only marginally improved outcomes in patients with HF. Fourth, cloning of NKA in 1985 revealed multiple NKA α and β subunit isoforms that, in the rodent, differ in their sensitivities to CTS. Fifth, the NKA is a cation pump and a hormone receptor/signal transducer. EO binding to NKA activates, in a ligand- and cell-specific manner, several protein kinase and Ca2+-dependent signaling cascades that have widespread physiological effects and can contribute to hypertension and HF pathogenesis. Sixth, all CTS are not equivalent, e.g., ouabain induces hypertension in rodents while digoxin is antihypertensinogenic ("biased signaling"). Seventh, most common rodent hypertension models require a highly ouabain-sensitive α2 NKA and the elevated blood pressure is alleviated by EO immunoneutralization. These numerous phenomena are enabled by NKA's intricate structure. We have just begun to understand the endocrine role of the endogenous ligands and the broad impact of the ouabain-binding site on physiology and pathophysiology. [ABSTRACT FROM AUTHOR]

Background and Objectives: Acute kidney injury (AKI) remains a significant complication following major cardiac surgery. Marinobufagenin (MBG), a cardiotonic steroid involved in sodium balance and blood pressure regulation, has been linked to organ damage after ischemia–reperfusion events. This pilot, prospective study investigates the utility of circulating MBG to improve AKI risk assessment in cardiac surgery patients as a stand-alone biomarker and after inclusion in a validated risk model (STS-AKI score). Materials and Methods: We included 45 patients undergoing elective cardiac surgery. The MBG levels were measured preoperatively and at 4, 8, and 12 h post-surgery. The AKI was defined according to the KDIGO guidelines. Statistical analyses assessed the diagnostic and prognostic utility of MBG and its integration with the STS-AKI score. Results: An AKI occurred in 26.7% of the patients. The STS-AKI score performed well in this cohort (AUC: 0.736). The MBG levels displayed a decreasing trend in the whole population after surgery (p = 0.02). However, in the AKI patients, MBG increased at 4 and 8 h before decreasing at 12 h post-surgery. The MBG changes from the baseline to 8 h and from 8 to 12 h post-surgery showed a remarkable diagnostic accuracy for an AKI (AUCs: 0.917 and 0.843, respectively). Integrating these MBG changes with the STS-AKI score significantly improved the model performance, including discrimination, calibration, and risk reclassification. Conclusions: The MBG measurement, particularly any dynamic changes post-surgery, enhances AKI risk stratification in cardiac surgery patients. Integrating MBG with the STS-AKI score offers more accurate risk predictions, potentially leading to better patient management and outcomes.

Preeclampsia (PE), the most severe presentation of hypertensive disorders of pregnancy, is the major cause of morbidity and mortality linked to pregnancy, affecting both mother and fetus. Despite advances in prophylaxis and managing PE, delivery of the fetus remains the only causative treatment available. Focus on complex pathophysiology brought the potential for new treatment options, and more conservative options allowing reduction of feto-maternal complications and sequelae are being investigated. Endogenous digitalis-like factors, which have been linked to the pathogenesis of preeclampsia since the mid-1980s, have been shown to play a role in the pathogenesis of various cardiovascular diseases, including congestive heart failure and chronic renal disease. Elevated levels of EDLF have been described in pregnancy complicated by hypertensive disorders and are currently being investigated as a therapeutic target in the context of a possible breakthrough in managing preeclampsia. This review summarizes mechanisms implicating EDLFs in the pathogenesis of preeclampsia and evidence for their potential role in treating this doubly life-threatening disease. [ABSTRACT FROM AUTHOR]

Background and Objectives: The global prevalence of chronic kidney disease (CKD) is on the rise, posing important challenges for healthcare systems. Thus, the search for new factors potentially involved in the pathogenesis, progression and complications of early CKD remains urgent. Marinobufagenin (MBG) is a natriuretic endogenous cardiotonic steroid, and increased circulating levels of it may accelerate kidney damage. In this study, we explored the possible clinical significance of measuring urinary marinobufagenin (uMBG) in patients with non-advanced CKD. Materials and Methods: One hundred and eight adult CKD patients (mean age 71.6 ± 10 years, 70.4% male; mean eGFR 40.54 ± 17 mL/min/1.73 m2) were enrolled in this cross-sectional study. uMBG was measured together with a series of clinical, anthropometric, laboratory and instrumental analyses. Twenty-five healthy matched subjects served as controls for the uMBG measurement. Results: The uMBG values were lower in the patients with CKD as compared to those of the controls (0.37 [IQR: 0.25–0.45] vs. 0.64 [0.46–0.78] nmol/L. p = 0.004), and a significant trend in eGFR levels was noticed across the decreasing uMBG tertiles (p = 0.03). Regarding the correlation analyses, the uMBG values remained robustly associated with the eGFR in multivariate models employing either uMBG or eGFR as the dependent variable (β = 0.248; p = 0.01 and β = 0.139; p = 0.04, respectively). Besides the eGFR, the independent predictors of uMBG values in this population were the use of statins (β = −0.326; p = 0.001), the presence of diabetes (β = 0.243; p = 0.009) and urine sodium (β = 0.204; p = 0.01). Conclusions: Reduced uMBG excretion may reflect impaired renal clearance, which may contribute to the detrimental effects attributed to this hormone due to systemic accumulation. Future studies are needed to clarify the biological mechanisms placing uMBG at the crossroad of sodium intake and the presence of diabetes in CKD-suffering individuals and to verify whether a statin treatment may somewhat limit the detrimental effects of MBG in the presence of impaired renal function. [ABSTRACT FROM AUTHOR]

Background: Left ventricular hypertrophy (LVH), which is a pervasive complication of end-stage kidney disease (ESKD), persists in some uremic individuals even after kidney transplantation (Ktx), contributing to worsening CV outcomes. Marinobufagenin (MBG), an endogenous steroid cardiotonic hormone endowed with natriuretic and vasoconstrictive properties, is an acknowledged trigger of uremic cardiomyopathy. However, its clinical significance in the setting of Ktx remains undefined. Methods: In a cohort of chronic Ktx recipients (n = 40), we assessed circulating MBG together with a thorough clinical and echocardiographic examination. Forty matched haemodialysis (HD) patients and thirty healthy subjects served as controls for MBG measurements. Patients were then prospectively followed up to 12 months and the occurrence of an established cardio-renal endpoint (death, CV events, renal events, graft rejection) was recorded. Results: Median MBG plasma levels were lower in Ktx as compared with HD patients (p = 0.02), but higher as compared with healthy controls (p = 0.0005). Urinary sodium (β = 0.423; p = 0.01) and eGFR (β = −0.324; p = 0.02) were the sole independent predictors of MBG in this cohort, while a strong correlation with left ventricular mass index (LVMi), found in univariate analyses (R = 0.543; p = 0.0007), gained significance only in multivariate models not including eGFR. Logistic regression analyses indicated MBG as a significant predictor of the combined endpoint (OR 2.38 [1.10–5.12] per each 1 nmoL/L increase; p = 0.01), as well as eGFR, LVMi, serum phosphate and proteinuria. Conclusions: Ktx recipients display altered MBG levels which are influenced by sodium balance, renal impairment and the severity of LVH. Thus, MBG might represent an important missing link between reduced graft function and pathological cardiac remodelling and may hold important prognostic value for improving cardio-renal risk assessment. [ABSTRACT FROM AUTHOR]

Purpose: Left ventricular hypertrophy (LVH) is remarkably prevalent among end-stage kidney disease (ESKD) on chronic dialysis and has a strong prognostic value for adverse outcomes. In experimental models, the endogenous cardiotonic steroid Marinobufagenin (MBG) promotes cardiac hypertrophy and accelerates uremic cardiomyopathy. In this study, we investigated the possible relationships between MBG, LV geometry and cardiac dysfunction in a clinical setting of ESKD. Methods: Plasmatic MBG was measured in 46 prevalent ESKD patients (n = 30 HD, n = 16 PD) together with a thorough laboratory, clinical, bioimpedance and echocardiography assessment. Different patterns of LV geometry were defined by left ventricular mass index (LVMi) and ventricular morphology. Diastolic dysfunction was diagnosed by the ASE/EACVI criteria. Results: MBG levels were significantly higher in ESKD patients than in healthy controls (p = 0.001) and more elevated in PD than in HD (p = 0.02). At multivariate analyses, E/eʹ (β = 0.38; p = 0.009) and LVMi (β = 0.42; p = 0.02) remained the sole independent predictors of MBG. A statistically significant trend in MBG levels (p = 0.01) was noticed across different patterns of LV geometry, with the highest values found in eccentric LVH. MBG levels were higher in the presence of diastolic dysfunction (p = 0.01) and this substance displayed a remarkable diagnostic capacity in distinguish patients with normal LV geometry, LV hypertrophy and, particularly, eccentric LVH (AUC 0.888; p < 0.0001) and diastolic dysfunction (AUC 0.79; p = 0.001). Conclusions: Deranged plasma MBG levels in ESKD patients on chronic dialysis reflect alterations in LV structure and function. MBG may, thus, candidate as a novel biomarker for improving cardiac assessment in this high-risk population. [ABSTRACT FROM AUTHOR]

BACKGROUND Previously we demonstrated that in patients with preeclampsia elevated levels of endogenous Na/K-ATPase inhibitor, marinobufagenin, cause inhibition of Friend leukemia virus integration 1 (Fli1), a negative regulator of collagen-1 synthesis. We hypothesized that in vitro silencing of Fli1 in healthy human umbilical arteries would be associated with an increase in collagen-1 output, similar to the effect of preeclampsia in rat and human tissues. METHODS The isolated segments of healthy human umbilical arteries were tested for sensitivity to MBG and Fli1 silencing with Fli1 siRNA or control siRNA. RESULTS Following 24-hour incubation of arteries with nanomolar concentrations of marinobufagenin, Fli1 expression was inhibited 5-fold (P < 0.001), and synthesis of collagen-1 increased 3 times (P < 0.01). Twenty-four-hour incubation of umbilical artery fragments with Fli1 siRNA caused a dramatic decrease of Fli1 (7-fold; P < 0.001) and cytoplasmic PKC δ (4-fold; P < 0.001) expression in comparison to control siRNA or untreated control, followed by elevation in procollagen (3-fold; P < 0.001) and collagen-1 (3-fold; P < 0.001) levels in vascular tissue. CONCLUSIONS Our results show that after silencing the Fli1 gene in healthy human umbilical arteries a new phenotype emerges which is typical for preeclampsia and is associated with vascular fibrosis. [ABSTRACT FROM AUTHOR]

Background and Objectives: The global prevalence of chronic kidney disease (CKD) is on the rise, posing important challenges for healthcare systems. Thus, the search for new factors potentially involved in the pathogenesis, progression and complications of early CKD remains urgent. Marinobufagenin (MBG) is a natriuretic endogenous cardiotonic steroid, and increased circulating levels of it may accelerate kidney damage. In this study, we explored the possible clinical significance of measuring urinary marinobufagenin (uMBG) in patients with non-advanced CKD. Materials and Methods: One hundred and eight adult CKD patients (mean age 71.6 ± 10 years, 70.4% male; mean eGFR 40.54 ± 17 mL/min/1.73 m2) were enrolled in this cross-sectional study. uMBG was measured together with a series of clinical, anthropometric, laboratory and instrumental analyses. Twenty-five healthy matched subjects served as controls for the uMBG measurement. Results: The uMBG values were lower in the patients with CKD as compared to those of the controls (0.37 [IQR: 0.25–0.45] vs. 0.64 [0.46–0.78] nmol/L. p = 0.004), and a significant trend in eGFR levels was noticed across the decreasing uMBG tertiles (p = 0.03). Regarding the correlation analyses, the uMBG values remained robustly associated with the eGFR in multivariate models employing either uMBG or eGFR as the dependent variable (β = 0.248; p = 0.01 and β = 0.139; p = 0.04, respectively). Besides the eGFR, the independent predictors of uMBG values in this population were the use of statins (β = −0.326; p = 0.001), the presence of diabetes (β = 0.243; p = 0.009) and urine sodium (β = 0.204; p = 0.01). Conclusions: Reduced uMBG excretion may reflect impaired renal clearance, which may contribute to the detrimental effects attributed to this hormone due to systemic accumulation. Future studies are needed to clarify the biological mechanisms placing uMBG at the crossroad of sodium intake and the presence of diabetes in CKD-suffering individuals and to verify whether a statin treatment may somewhat limit the detrimental effects of MBG in the presence of impaired renal function.

The hypertensive response in Dahl salt-sensitive (DSS) rats on a high-salt (HS) diet is accompanied by central arterial stiffening (CAS), a risk factor for dementia, and heightened levels of a prohypertensive and profibrotic factor, the endogenous Na/K-ATPase inhibitor marinobufagenin (MBG). We studied the effect of the in vivo administration of MBG or HS diet on blood pressure (BP), CAS, and behavioral function in young DSS rats and normotensive Sprague–Dawley rats (SD), the genetic background for DSS rats. Eight-week-old male SD and DSS rats were given an HS diet (8% NaCl, n = 18/group) or a low-salt diet (LS; 0.1% NaCl, n = 14–18/group) for 8 weeks or MBG (50 µg/kg/day, n = 15–18/group) administered via osmotic minipumps for 4 weeks in the presence of the LS diet. The MBG-treated groups received the LS diet. The systolic BP (SBP); the aortic pulse wave velocity (aPWV), a marker of CAS; MBG levels; spatial memory, measured by a water maze task; and tissue collection for the histochemical analysis were assessed at the end of the experiment. DSS-LS rats had higher SBP, higher aPWV, and poorer spatial memory than SD-LS rats. The administration of stressors HS and MBG increased aPWV, SBP, and aortic wall collagen abundance in both strains vs. their LS controls. In SD rats, HS or MBG administration did not affect heart parameters, as assessed by ECHO vs. the SD-LS control. In DSS rats, impaired whole-heart structure and function were observed after HS diet administration in DSS-HS vs. DSS-LS rats. MBG treatment did not affect the ECHO parameters in DSS-MBG vs. DSS-LS rats. The HS diet led to an increase in endogenous plasma and urine MBG levels in both SD and DSS groups. Thus, the prohypertensive and profibrotic effect of HS diet might be partially attributed to an increase in MBG. The prohypertensive and profibrotic functions of MBG were pronounced in both DSS and SD rats, although quantitative PCR revealed that different profiles of profibrotic genes in DSS and SD rats was activated after MBG or HS administration. Spatial memory was not affected by HS diet or MBG treatment in either SD or DSS rats. Impaired cognitive function was associated with higher BP, CAS, and cardiovascular remodeling in young DSS-LS rats, as compared to young SD-LS rats. MBG and HS had similar effects on the cardiovascular system and its function in DSS and SD rats, although the rate of change in SD rats was lower than in DSS rats. The absence of a cumulative effect of increased aPWV and BP on spatial memory can be explained by the cerebrovascular and brain plasticity in young rats, which help the animals to tolerate CAS elevated by HS and MBG and to counterbalance the profibrotic effect of heightened MBG. [ABSTRACT FROM AUTHOR]

Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Recently, we demonstrated that (i) MBG induces fibrosis in rat tissues via a mechanism involving Fli1, a negative regulator of collagen-1 synthesis, and (ii) MBG sensitive Na/K-ATPase inhibition is reversed by mineralocorticoid antagonists. We hypothesized that in human PE elevated MBG level is associated with the development of fibrosis of the umbilical arteries and that this fibrosis can be attenuated by canrenone. Fifteen patients with PE (mean BP = 118 ± 4 mmHg; 34 ± 2 years; 38 ± 0.3 weeks gest. age) and twelve gestational age-matched normal pregnant subjects (mean BP = 92 ± 2 mmHg; 34 ± 1 years; 39 ± 0.2 weeks gest. age) were enrolled in the study. PE was associated with a higher plasma MBG level, with a four-fold decrease in Fli1 level and a three-fold increase in collagen-1 level in the PE umbilical arteries vs. those from the normal subjects (p < 0.01). Isolated rings of umbilical arteries from the subjects with PE exhibited impaired responses to the relaxant effect of sodium nitroprusside vs. control vessels (EC50 = 141 nmol/L vs. EC50 = 0.9 nmol/L; p < 0.001). The effects of PE on Fli1 and collagen-1 were blocked by the in vitro treatment of umbilical arteries by 10 μmol/L canrenone. Similar results were obtained for umbilical arteries pretreated with MBG. These data demonstrate that elevated MBG level is implicated in the development of the fibrosis of umbilical arteries in PE, and that this could be blocked by mineralocorticoid antagonists. [ABSTRACT FROM AUTHOR]