marinobufagenin and Kidney-Diseases

Endogenous cardiotonic steroids (CTS), also called digitalis-like factors, are a group of steroid hormones linking high salt intake and elevated blood pressure and in part responsible for target organ damage in arterial hypertension. CTS act primarily through their ability to inhibit the ubiquitous transport enzyme sodium-potassium adenosine triphosphatase (Na⁺/K⁺-ATPase). A portion of Na⁺/K⁺-ATPase does not seem to actively "pump" sodium and potassium but is closely associated with other key signaling proteins. Plasma concentration and urine excretion of CTS are increased in experimental models with volume expansion and on a high salt diet. Elevated plasma concentration of marinobufagenin has been shown in volume-expanded states such as essential hypertension, primary aldosteronism, chronic renal failure, congestive heart failure and pregnancy. In experimental models marinobufagenin induces heart and kidney fibrosis to the same extent as observed in uremia. Neutralization of marinobufagenin with antibodies prevents such heart remodeling. Expanding our understanding of this new class of hormones may lead to development of novel and effective therapeutic strategies in hypertensive patients with renal and cardiovascular complications.

Topics: Animals; Blood Pressure; Bufanolides; Cardenolides; Cardiac Glycosides; Cardiotonic Agents; Humans; Hypertension; Kidney Diseases; Saponins; Sodium-Potassium-Exchanging ATPase; Ventricular Remodeling

Cardiotonic steroids (CTS) are Na⁺/K⁺-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1

Topics: Animals; Bufanolides; Cell Line; Fibrosis; Glycogen Synthase Kinase 3 beta; Kidney Diseases; MAP Kinase Signaling System; Mice; Ouabain; Phosphorylation; Signal Transduction; Sodium-Potassium-Exchanging ATPase; Swine

We have shown that the cardiotonic steroid marinobufagenin (MBG) is elevated in clinical and experimental renal disease, and significantly contributes to the development of experimental uremic cardiomyopathy induced by removal of five-sixths of the kidney (5/6 nephrectomy; PNx) in the rat. We have demonstrated that both active and passive immunization against MBG with an anti-MBG monoclonal antibody (mAb 3E9) significantly attenuated cardiac fibrosis following PNx. In the present study we sought to determine whether the use of mAb 3E9 could improve renal function following PNx.. Sprague-Dawley rats were treated with either mAb 3E9 or with DigiFab (an affinity-purified anti-digoxin antibody formerly named Digibind) during the fourth week after PNx. Sham-operated animals and PNx animals treated with an IgG antibody served as controls. Plasma, urine, and renal tissue were collected at the completion of the study to determine the effects of antibody treatment on renal function.. In PNx rats, treatments with mAb 3E9 and DigiFab, respectively, significantly reduced plasma creatinine, improved creatinine clearance, and reduced proteinuria below the values of these three measures in IgG-treated PNx controls. Additionally, treatment with mAb 3E9 and DigiFab significantly reduced renal fibrosis as measured with Western blotting and Sirius red/Fast green staining.. Passive immunization against MBG significantly improved renal function and markedly reduced renal fibrosis following the experimental induction of renal disease. The work in the study reported here adds to a growing body of knowledge implicating MBG in the development of chronic renal disease. Passive immunization against cardiotonic steroids may serve as a promising treatment for chronic renal disease.

Topics: Animals; Antibodies, Monoclonal; Bufanolides; Cardiac Glycosides; Fibrosis; Immunization, Passive; Immunoglobulin Fab Fragments; Kidney; Kidney Diseases; Male; Nephrectomy; Rats; Rats, Sprague-Dawley

We recently demonstrated that the cardiotonic steroid marinobufagenin (MBG) induced fibrosis in rat hearts through direct stimulation of collagen I secretion by cardiac fibroblasts. This stimulation was also responsible for the cardiac fibrosis seen in experimental renal failure. In this study, the effect of MBG on the development of renal fibrosis in rats was investigated. Four weeks of MBG infusion triggered mild periglomerular and peritubular fibrosis in the cortex and the appearance of fibrotic scars in the corticomedullary junction of the kidney. MBG also significantly increased the protein levels and nuclear localization of the transcription factor Snail in the tubular epithelia. It is known that activation of Snail is associated with epithelial-to-mesenchymal transition (EMT) during renal fibrosis. To examine whether MBG alone can trigger EMT, we used the porcine proximal tubular cell line LLC-PK1. MBG (100 nM) caused LLC-PK1 cells grown to confluence to acquire a fibroblast-like shape and have an invasive motility. The expressions of the mesenchymal proteins collagen I, fibronectin, and vimentin were increased twofold. However, the total level of E-cadherin remained unchanged. These alterations in LLC-PK1 cells in the presence of MBG were accompanied by elevated expression and nuclear translocation of Snail. During the time course of EMT, MBG did not have measurable inhibitory effects on the ion pumping activity of its natural ligand, Na(+)-K(+)-ATPase. Our data suggest that the MBG may be an important factor in inducing EMT and, through this mechanism, elevated levels of MBG in chronic renal failure may play a role in the progressive fibrosis.

Topics: Animals; Bufanolides; Cardiotonic Agents; Cell Movement; Cell Shape; Cell Transdifferentiation; Collagen Type I; Enzyme Inhibitors; Epithelial Cells; Fibronectins; Fibrosis; Infusion Pumps, Implantable; Kidney; Kidney Diseases; LLC-PK1 Cells; Male; Mesoderm; Ouabain; Rats; Rats, Sprague-Dawley; Signal Transduction; Snail Family Transcription Factors; Sodium-Potassium-Exchanging ATPase; Swine; Time Factors; Transcription Factors; Vimentin