Monoclonal antibody against marinobufagenin reverses cardiac fibrosis in rats with chronic renal failure

• Published in: American journal of hypertension 2012-06, Vol.25 (6), p.690-696
• Main Authors: Haller, Steven T., Kennedy, David J., Shidyak, Amjad, Budny, George V., Malhotra, Deepak, Fedorova, Olga V., Shapiro, Joseph I., Bagrov, Alexei Y.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Blood Pressure - physiology; Bufanolides - immunology; Bufanolides - metabolism; Cardiology. Vascular system; Cardiomegaly - etiology; Cardiomegaly - metabolism; Cardiomegaly - prevention & control; Comorbidity; Disease Models, Animal; Experimental diseases; Fibrosis; Immunoglobulin Fab Fragments - pharmacology; Immunoglobulin Fab Fragments - therapeutic use; Kidney Failure, Chronic - complications; Kidney Failure, Chronic - metabolism; Kidney Failure, Chronic - surgery; Male; Medical sciences; Myocardium - metabolism; Myocardium - pathology; Nephrectomy; Proto-Oncogene Protein c-fli-1 - metabolism; Rats; Rats, Sprague-Dawley
• ISSN: 0895-7061; 1941-7225; 1879-1905
• DOI: 10.1038/ajh.2012.17

Background Cardiotonic steroids (CTS) are implicated in pathophysiology of uremic cardiomyopathy. In the present study, we tested whether a monoclonal antibody (mAb) against the bufadienolide CTS, marinobufagenin (MBG), alleviates cardiac hypertrophy and fibrosis in partially nephrectomized (PNx) rats. Methods In PNx rats, we compared the effects of 3E9 anti-MBG mAb and of Digibind, an affinity-purified digoxin antibody, on blood pressure and cardiac hypertrophy and fibrosis following 4 weeks after the surgery. Results In PNx rats, a fourfold elevation in plasma MBG levels was associated with hypertension, increased cardiac levels of carbonylated protein, cardiac hypertrophy, a reduction in cardiac expression of a nuclear transcription factor which is a negative regulator of collagen synthesis, Friend leukemia integration-1 (Fli-1), and an increase in the levels of collagen-1. A single intraperitoneal administration of 3E9 mAb to PNx rats reduced blood pressure by 59 mm Hg for 7 days and produced a significant reduction in cardiac weight and cardiac levels of oxidative stress, an increase in the expression of Fli-1, and a reduction in cardiac fibrosis. The effects of Digibind were similar to those of 3E9 mAb, but were less pronounced. Conclusions In experimental chronic renal failure, elevated levels of MBG contribute to hypertension and induce cardiac fibrosis via suppression of Fli-1, representing a potential target for therapy.