Sodium pump inhibitors in blood pressure regulation and in profibrotic signaling in salt sensitive hypertension and aging

有两种促纤维化途径，Fli 1依赖性和TGF-β依赖性，其在动物慢性肾病模型、糖尿病和衰老以及培养的大鼠血管平滑肌细胞和心肌细胞中被MBG激活。在高血压Dahl盐敏感大鼠和血压正常的Sprague-Dawley大鼠的心血管和肾组织中，在高盐摄入的情况下，通过升高的MBG激活TGF-β依赖性途径。我们在动物模型和培养的大鼠心肌细胞和血管平滑肌细胞中证明：（i）Fli 1依赖性和TGF-β依赖性促纤维化途径在磷酸化PKC-δ水平上表现出串扰;（ii）这些途径独立或同时激活;（iii）促纤维化信号传导的激活不依赖于BP。 实验1.本研究入组了34例接受联合（赖诺普利/双氢克尿噻/氢氯噻嗪）治疗的RH患者（18例男性和16例女性; 568岁）和11例年龄匹配的健康血压正常受试者（7例男性和4例女性; 542岁）。采用Sphygmocor Px装置测量动脉硬度，计算PWV。测定红细胞钠泵活性。我们证明，在RH患者与血压正常的对照组中，适度的氯化钠给药对MBG的反应与动脉血压无关，而与PWV以性别和年龄特异性的方式相关。 实验2.这项临床研究包括711名参与者的数据（黑人51%，男性42%，平均年龄24.83.0岁）。测定颈动脉-股动脉脉搏波传导速度（cfPWV）、24 h尿MBG和尿钠排泄量。在单因素、部分因素和多因素调整回归分析中，我们发现年轻女性cfPWV和MBG排泄之间存在持续的正相关性，但男性则不然。多元回归模型根据种族、年龄、腰围身高比、平均动脉血压、高密度脂蛋白胆固醇、C反应蛋白、谷氨酰转移酶和葡萄糖进行校正。总之，在年轻时，内源性MBG水平升高可能通过压力无关机制导致女性大动脉僵硬，增加未来心血管疾病的风险。 最近的研究结果表明，24小时尿MBG与年轻健康成人（年龄20-30岁）的习惯性盐摄入量密切相关。此外，在没有检测到心血管疾病的年轻健康成人中，MBG与独立于血压的大动脉硬度和左心室质量增加相关。这些在人体研究中的发现证实了来自大鼠研究的机制数据，其中通过高盐摄入或MBG输注刺激MBG增加了血管纤维化和心脏肥大。24小时尿MBG可能是早期心血管风险的潜在生物标志物。MBG（随盐摄入量增加）与早期心血管风险标志物之间的不良关联支持全球减少全民盐摄入量的努力，以预防和控制非传染性疾病的负担。 结论：这些在人体研究中的发现证实了来自大鼠研究的机制数据，其中通过高盐摄入或MBG输注刺激MBG增加了血管纤维化和心脏肥大。MBG是盐敏感性的标志物，可能是早期心血管风险的潜在生物标志物。

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. 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. Experiment 2. 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. Recent findings demonstrated that 24-hour urinary MBG strongly associates with habitual salt intake in young healthy adults (aged 20-30 years). Furthermore, in young healthy adults free of detected cardiovascular disease, MBG associates with increased large artery stiffness and left ventricular mass independent of blood pressure. 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. Twenty-four-hour urinary MBG may be a potential biomarker of early cardiovascular risk. Adverse associations between MBG, which increases with salt consumption,and early cardiovascular risk markers support the global efforts to reduce population-wide salt intake in an effort to prevent and control the burden of non-communicable diseases. 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.