marinobufagenin and Proteinuria

Levels of leptin and marinobufagenin (MBG), a cardiotonic steroid, are elevated in the serum of women with pre-eclampsia. Besides this, leptin administration to pregnant rats increases systolic blood pressure (SBP), urinary protein excretion and serum markers of endothelial activation. The link between leptin and MBG is unknown and it is also unclear if leptin-induced increases in blood pressure and proteinuria in the pregnant rat could be prevented by an MBG antagonist. To ascertain this link, this study investigated the effect of resibufogenin (RBG), a marinobufagenin antagonist, on leptin-induced increases in blood pressure and proteinuria during pregnancy in rats. Four groups of Sprague-Dawley rats, aged 12 weeks, were given either normal saline (CONTROL) or 120 μg/kg/day of leptin (LEP), or 120 μg/kg/day of leptin+30 μg/kg/day of resibufogenin (L + RBG) or 30 μg/kg/day of resibufogenin (RBG) from Day 1-20 of pregnancy. Systolic blood pressure and urinary protein excretion (UPE) were measured during the study period. Animals were euthanized on day 21 of pregnancy and vascular cell adhesion molecule 1, (VCAM-1), soluble intracellular cell adhesion molecule 1 (sICAM-1), E-selectin and endothelin-1 (ET-1) were estimated in the serum. SBP, UPE, VCAM-1, sICAM-1 and ET-1 were significantly higher only in the LEP group when compared with those in CONT and in L + RBG and RBG groups. The prevention by RBG of leptin-induced increases in SBP, proteinuria, and endothelial activation during pregnancy seem to suggest a potential role for MBG in leptin-induced adverse effects on blood pressure, urinary protein excretion and endothelial activity during pregnancy in the rat.

Topics: Animals; Blood Pressure; Bufanolides; Endothelin-1; Endothelium, Vascular; Female; Intercellular Adhesion Molecule-1; Leptin; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Vascular Cell Adhesion Molecule-1

Marinobufagenin (MBG) is an endogenous cardiotonic steroid (CTS) that inhibits the Na+/K+-ATPase. Human MBG is significantly increased in end-stage renal disease and immunization against MBG attenuates cardiovascular fibrosis in a rat model of uremic cardiomyopathy. Mineralocorticoid antagonists (MRA) block MBG binding sites and decrease proteinuria in chronic kidney disease (CKD) patients. We therefore aimed to investigate the association of MBG and albuminuria, as a marker of renal damage, as well as MBG and decline of glomerular filtration rate (GFR).. The Graz endocrine causes of hypertension (GECOH) study is a single center study of adults routinely referred for screening of endocrine hypertension. Plasma MBG was measured by an enzyme-linked immunoassay, and in a post-hoc analysis, follow-up creatinine levels were obtained. Patients with proteinuria >3.5g/day at baseline were excluded from further evaluation.. We measured MBG concentrations in 40 hypertensive subjects and excluded one patient due to pre-existing proteinuria. Plasma MBG was significantly correlated with albuminuria (Spearman ρ = .357; p = .028) and proteinuria (ρ = .336; p = .039). In linear regression analysis, the association remained significant after adjustment for age, sex, and BMI (β = .306; p = .036), and for mean systolic blood pressure (β = .352; p = .034). In follow-up analyses (N = 30), MBG was significantly associated with decline in GFR after adjustment for time-to-follow-up (β = -.374; p = .042).. The findings suggest that MBG plasma concentrations were associated with albuminuria as well as decline in kidney function. Whether MBG predicts hard renal endpoints warrants further investigations.

Topics: Adult; Aged; Albuminuria; Animals; Biomarkers; Bufanolides; Cardiotonic Agents; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Proteinuria; Rats; Renal Insufficiency, Chronic

Previous studies from this laboratory have demonstrated that the bufodienolide, marinobufagenin, causes a syndrome in the pregnant rat that resembles human preeclampsia. Furthermore, marinobufagenin urinary excretion is elevated in approximately 85% of preeclamptic patients. Resibufagenin, an antagonist to marinobufagenin, completely prevents the syndrome (hypertension, proteinuria, and intrauterine growth restriction) if given from early pregnancy.. We investigated the effects of another bufodienolide, cinobufatalin, to determine if it, likewise, could induce the rat "preeclamptic" syndrome, which it did. We then examined whether resibufagenin could prevent the syndrome due to cinobufatalin.. Resibufagenin improved hypertension but not proteinuria, and did not prevent uterine growth restriction.. We conclude that more than one bufodienolide may induce the preeclamptic syndrome and that each may require a specific antagonist to prevent (or treat) the syndrome.

Topics: Animals; Bufanolides; Disease Models, Animal; Female; Fetal Growth Retardation; Hypertension; Pre-Eclampsia; Pregnancy; Proteinuria; Rats

Preeclampsia (PE) is a disorder that results in significant fetomaternal morbidity and mortality with yet no definitive pharmacological intervention. It involves the development of de novo hypertension and proteinuria after 20 weeks of pregnancy. All too often, intrauterine growth restriction (IUGR) occurs. Evidence has accrued that implicates the cardiac glycosides (the cardenolides and the bufadienolides) as potentially involved in the pathophysiology of PE. These compounds act by inhibiting Na(+)/K(+) ATPase. Digibind (digoxin immune Fab) antagonizes this action of the cardenolides. It also has cross-reactivity against the bufadienolides, including marinobufagenin. This study investigated the effects of Digibind in a rat model of PE. We induced a syndrome in rats, which includes many of the phenotypic characteristics of human PE. Digibind, in escalating doses, was given on days 10 to 20 of pregnancy. Digibind produced significant lowering of the blood pressure and reduced proteinuria in our rat model of PE. However, it also did not avert IUGR. In view of these findings, in our experimental model of human PE, further studies in the quest for effective treatment of PE need to focus on pharmaceuticals that can remedy the syndrome without compromising the fetus.

Topics: Animals; Animals, Newborn; Blood Pressure Determination; Bufanolides; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fetal Growth Retardation; Immunoglobulin Fab Fragments; Injections, Intraperitoneal; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Probability; Proteinuria; Random Allocation; Rats; Reference Values; Risk Assessment; Treatment Outcome; Urinalysis

The bufodienolides are cardiac glycosides which have the ability to inhibit the enzyme, Na(+)/K(+) ATPase (sodium potassium adenosine triphosphatase). They are cardiac inotropes, cause vasoconstriction (and, potentially, hypertension) and are natriuretic. Evidence has accrued over time which supports the view that they are mechanistically involved in volume expansion-mediated hypertension. In this communication, the authors summarize data which support the view that the bufodienolides and, in particular, marinobufagenin (MBG) are involved in the pathogenesis of preeclampsia. In a rat model of the syndrome, MBG causes hypertension, proteinuria, intrauterine growth restriction and increased weight gain. All of these phenotypic characteristics are prevented by an antagonist to MBG, resibufogenin (RBG). The "preeclamptic" animals also develop a vascular leak syndrome, resulting in hemoconcentration. Abnormalities in the MAPK (mitogen-activated protein kinase) system play a role in the mechanism by which MBG produces the abnormalities in the pregnant rat. Studies to discover the relevance of these findings to human preeclampsia are currently underway in several laboratories and clinics.

Topics: Animals; Bufanolides; Disease Models, Animal; Female; Fetal Growth Retardation; Humans; Mitogen-Activated Protein Kinase Kinases; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Sodium-Potassium-Exchanging ATPase

Pre-eclampsia is a disorder that results in significant feto-maternal complications with yet no definitive pharmacologic intervention. One postulated etiologic mechanism is an imbalance between circulating pro-angiogenic and anti-angiogenic factors. We investigated these factors sequentially throughout pregnancy (19-21 days) in our rat model of pre-eclampsia, which involves the imposition of excessive volume expansion.. We evaluated the status of the pro-angiogenic and anti-angiogenic factors at the following time points: 3-5, 7-10 and 17-20 days of gestation.. We have previously determined that the urinary excretion of the circulating bufodienolide, marinobufagenin, is elevated at the 3- to 5-day time period, prior to the advent of hypertension and proteinuria. At 3-5 days of pregnancy, there was no evidence of angiogenic imbalance in the normal pregnant (NP) and 'pre-eclamptic' (PDS) rats. At the 7- to 10-day time point, plasma PlGF was greater in the NP rats than in the PDS group (p < 0.05). The plasma sFlt-1/PlGF ratio in the PDS animals was greater than that in the NP rats (p < 0.05). The placental sFlt-1 and sFlt-1/PlGF ratio were greater in the PDS rats than in NP rats (p < 0.05). These changes were also present at the 17- to 20-day time point in both plasma and placenta. The administration of resibufogenin, an antagonist of marinobufagenin, early in pregnancy, prevented angiogenic imbalance.. We conclude that angiogenic imbalance plays a role in the pathogenesis of pre-eclampsia in this rat model. Furthermore, the earliest event in the pathogenetic sequence appears to be the secretion and elaboration of marinobufagenin.

Topics: Analysis of Variance; Angiogenic Proteins; Animals; Blood Pressure; Bufanolides; Creatinine; Endoglin; Female; Gestational Age; Hematocrit; Intracellular Signaling Peptides and Proteins; Models, Animal; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Proteinuria; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

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