Endogenous bufadienolides, mineralocorticoid receptor antagonists and fibrosis in chronic kidney disease.

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.

Antibody to Endogenous Cardiotonic Steroid Reverses Vascular Fibrosis and Restores Vasorelaxation in Chronic Kidney Disease.

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.

Silencing of Gene Mimics Effect of Aging and Sensitizes Rat Vascular Smooth Muscle Cells to Cardiotonic Steroids: Impact on Fibrosis and Salt Sensitivity.

Background Marinobufagenin, NKA (Na/K-ATPase) inhibitor, causes vasoconstriction and induces fibrosis via inhibition of Fli1 (Friend leukemia integration-1), a negative regulator of collagen synthesis. In vascular smooth muscle cells (VSMC), ANP (atrial natriuretic peptide), via a cGMP/PKG1 (protein kinase G1)-dependent mechanism, reduces NKA sensitivity to marinobufagenin. We hypothesized that VSMC from old rats, due to downregulation of ANP/cGMP/PKG-dependent signaling, would exhibit heightened sensitivity to the profibrotic effect of marinobufagenin.

Fli1 and Tissue Fibrosis in Various Diseases.

Being initially described as a factor of virally-induced leukemias, Fli1 (Friend leukemia integration 1) has attracted considerable interest lately due to its role in both healthy physiology and a variety of pathological conditions. Over the past few years, Fli1 has been found to be one of the crucial regulators of normal hematopoiesis, vasculogenesis, and immune response. However, abnormal expression of Fli1 due to genetic predisposition, epigenetic reprogramming (modifications), or environmental factors is associated with a few diseases of different etiology.

Silencing of Fli1 Gene Mimics Effects of Preeclampsia and Induces Collagen Synthesis in Human Umbilical Arteries.

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.