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

Abstract

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.

• Authors: Steven T Haller, David J Kennedy, Amjad Shidyak, George V Budny, Deepak Malhotra, Olga V Fedorova, Joseph I Shapiro, Alexei Y Bagrov
• Journal: American journal of hypertension (Am J Hypertens) Vol. 25 Issue 6 Pg. 690-6 (Jun 2012) ISSN: 1941-7225 [Electronic] United States
• PMID: 22378033 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Antibodies, Monoclonal
• Bufanolides
• Immunoglobulin Fab Fragments
• Proto-Oncogene Protein c-fli-1
• digoxin antibodies Fab fragments
• marinobufagenin

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Blood Pressure (drug effects, physiology)
• Bufanolides (immunology, metabolism)
• Cardiomegaly (etiology, metabolism, prevention & control)
• Comorbidity
• Disease Models, Animal
• Fibrosis
• Immunoglobulin Fab Fragments (pharmacology, therapeutic use)
• Kidney Failure, Chronic (complications, metabolism, surgery)
• Male
• Myocardium (metabolism, pathology)
• Nephrectomy
• Proto-Oncogene Protein c-fli-1 (metabolism)
• Rats
• Rats, Sprague-Dawley