Elevated levels of cardiotonic steroid marinobufagenin (MBG) are implicated in pathogenesis of salt-sensitive hypertension in Dahl-S rats (DS), and induce cardiac fibrosis in rats with experimental uremic cardiomyopathy. We hypothesized that in hypertensive DS immunoneutralization of MBG with a monoclonal antibody (Mab) would affect expression of profibrotic genes and would exhibit anti-remodeling effects. We studied following groups (n=6 each): (1) DS on a low salt (0.3% NaCl) diet (LS); (2) DS on a high salt (8% NaCl) diet for 7 weeks (HS); (3) DS on a high salt diet for 7 weeks, following 3E9 anti-MBG Mab treatment for 5 days (HSAB). Levels of MBG, and levels of mRNA expression in aorta (microarray analysis, Illumina) were assessed. In HS vs. LS, BP increased by 78 mmHg (p<0.01), plasma MBG doubled (p<0.05), renal MBG excretion increased 6-fold (p<0.01), and relative weights of aortae increased (4.44±0.17 vs. 3.01±0.06 mg/mm x kg BW, p<0.01). In HSAB, BP decreased by 35 mmHg (p<0.01), and weights of aortae were markedly reduced (3.72±0.06 mg/mm x kg BW; p<0.01) vs. HS. In hypertensive DS, genes implicated in TGFβ-signaling (Table) were up-regulated, and were down-regulated following immunoneutralization of MBG. Thus, MBG participates in vascular remodeling in DS, and immunoneutralization of MBG produces an anti-remodeling effect associated with down-regulation of genes implicated in TGFβ-induced pro-fibrotic signaling.
Table
. Z-ratio of paired analysis of gene expression in aorta:
GW25-e5146 High-salt diet decreases ACE2 and activates TGF-β1/Smads signaling pathway in vascular remodeling
