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

• Published in: International journal of molecular sciences 2024-08, Vol.25 (16), p.8896
• Main Authors: Agalakova, Natalia I, Mikhailova, Elena V, Ershov, Ivan A, Nadei, Olga V, Pyankov, Arseny A, Galagoudza, Michael M, Adair, C David, Romanova, Irina V, Bagrov, Alexei Y
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - pharmacology; Aorta - drug effects; Aorta - metabolism; Blood pressure; Bufanolides - pharmacology; Collagen; Collagen Type I - metabolism; Coronary vessels; Endothelin-1 - metabolism; Fibroblasts; Fibrosis; Kidney diseases; Kinases; Male; Monoclonal antibodies; Nephrectomy; Nitroprusside - pharmacology; Pathogenesis; Phosphorylation; Plasma; Preeclampsia; Proto-Oncogene Protein c-fli-1 - metabolism; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - metabolism; Transcription factors; Vasodilation - drug effects
• ISSN: 1661-6596; 1422-0067; 1422-0067
• DOI: 10.3390/ijms25168896

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. Sham-operated animals comprised the control group. At 5 weeks following nephrectomy, rats were administered the vehicle ( = 8), or the anti-MBG antibody ( = 8). Isolated aortic rings were tested for their responsiveness to sodium nitroprusside following endothelin-1-induced constriction. In nephrectomized rats, there was an increase in the intensity of collagen staining in the aortic wall vs. the controls. In antibody-treated rats, the structure of bundles of collagen fibers had ordered organization. Western blots of the aorta had lower levels of Fli1 (arbitrary units, 1 ± 0.05 vs. 0.2 ± 0.01; < 0.001) and greater collagen-1 (arbitrary units, 1 ± 0.01 vs. 9 ± 0.4; < 0.001) vs. the control group. Administration of the MBG antibody to rats reversed the effect of the nephrectomy on Fli1 and collagen-1 proteins. Aortic rings pretreated with endothelin-1 exhibited 50% relaxation following the addition of sodium nitroprusside (EC = 0.28 μmol/L). The responsiveness of the aortic rings obtained from nephrectomized rats was markedly reduced (EC = 3.5 mol/L) compared to the control rings. Treatment of rats with the antibody restored vasorelaxation. Thus, the anti-MBG antibody counteracts the Fli1-collagen-1 system and reduces aortic fibrosis.