Salt-sensitive hypertension is accompanied by elevated levels of an endogenous Na/K-ATPase inhibitor, marinobufagenin (MBG). Because MBG is implicated in cardiac fibrosis in experimental uremic cardiomyopathy (Hypertension 2007;49:215–24), we hypothesized that immunoneutralization of heightened levels of MBG in hypertensive Dahl salt-sensitive rats (DS) with monoclonal antibody may impact the profibrotic gene expression and cardiac remodeling.

We studied the following groups (n=6 each): (a) DS on a low salt (0.3% NaCl) diet (LS); (b) DS on a high salt (8% NaCl) diet for 7 weeks (HS); (c) DS on a high salt diet for 7 weeks, followed by monoclonal anti-MBG antibody treatment for 5 days (HSAB). Levels of MBG and of proteins implicated in pro-fibrotic signalling, and mRNA expression (microarray analysis) in left ventricles (LV) and aortae were assessed.

In HS vs. LS, BP increased by 74 mmHg (p<0.01), plasma MBG doubled (p<0.05), renal MBG excretion increased 6-fold (p<0.01), tissue weights increased (LV: 2.37±0.05 vs. 1.62±0.04 g/kg BW, p<0.01; aorta: 4.44±0.17 vs. 3.01±0.06 mg/mm^*kg BW, p<0.01), and LV collagen rose 3.5-fold. In HSAB, BP was reduced by 35 mmHg (p<0.01), collagen-1 and LV and aortic weights were reduced (p<0.01) vs. HS group. In hypertensive DS there was a tissue-specific pattern of up-regulation of expression of genes, implicated in TGFβ-signaling (LV: TGFβ1-β2, MAPK3, CTGF, SMADs, collagen-1; aorta: TGFβ1-β3, PDGF, fibronectin, SNAIL1, PCOLCE, collagens), that was down-regulated following immunoneutralization of MBG.

Thus, immunoneutralization of MBG produces an anti-remodeling effect associated with down-regulation of genes implicated in TGFβ-induced fibrosis initiated by MBG in salt-sensitive hypertension.