There are two pro-fibrotic pathways, Fli1-dependent and TGF-beta-dependent, which are activated by MBG in animal chronic kidney disease models, diabetes and aging, and in the cultured rat vascular smooth muscle cells and cardiac myocytes. The TGF-beta-dependent pathway is activated by heightened MBG in the presence of a high salt intake in cardiovascular and renal tissues from hypertensive Dahl salt-sensitive rats and normotensive Sprague-Dawley rats. We demonstrated in the animal models and in cultured rat cardiac myocytes and vascular smooth muscle cells (i) that Fli1-dependent and TGF-beta-dependent pro-fibrotic pathways exhibit a crosstalk at the level of phosphorylated PKC-delta, (ii) that these pathways are activated either independently, or simultaneously, and (iii) that the activation of the profibrotic signaling is BP independent. Experiment 1. This clinical study included data of 711 participants (black 51%, men 42%, mean age 24.83.0 years). We measured the carotidfemoral pulse wave velocity (cfPWV), 24-h urinary MBG and sodium excretion. In single, partial and multivariable adjusted regression analyses, we found a persistent positive association between cfPWV and MBG excretion in young women, but not men. Multiple regression models were adjusted for ethnicity, age, waist-to-height ratio, mean arterial BP, high-density lipoprotein cholesterol, C-reactive protein, glutamyl transferase and glucose. In conclusion, already at a young age heightened endogenous MBG levels may contribute to large artery stiffness in women via pressure-independent mechanisms, increasing their risk for future cardiovascular disease. Experiment 2. Thirty-four patients (18 males and 16 females; 568 years) with RH on a combined (lisinopril/amlodipine/hydrochlorothiazide) therapy and 11 healthy age-matched normotensive subjects (7 males and 4 females; 542 years) were enrolled in this study. Arterial stiffness was measured by Sphygmocor Px device with a calculation of PWV. Activity of Na pump was measured in erythrocytes. We demonstrated that the response of MBG on a moderate sodium chloride administration did not correlate with arterial BP and was associated with PWV in a gender- and age-specific fashion in RH patients vs. normotensive controls. Conclusion: These findings in human studies corroborate mechanistic data from rat studies whereby stimulation of MBG by a high salt intake or MBG infusion increased vascular fibrosis and cardiac hypertrophy. MBG is a marker of salt-sensitivity and may be a potential biomarker of early cardiovascular risk.
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