味觉受体TRPM5受损抑制盐味觉敏感性的机制研究

High salt is one of the major environmental factors of hypertension and stroke, and salt reduction is important for preventing hypertension. The salt taste changes play a key role in the regulation of salt intake. Excessive salt intake will activate the bitter taste and resulting in disgust feeling, but whether this physiological protection mechanism is damaged by high salt intake is not clear. We found significant reduction in sensitivity to bitter taste in people with long-term high salt intake. Long-term high salt diet decreased the salt taste sensitivity and inhibited the expression of TRPM5 in tongue epithelium in mice, which was significantly correlated with salt intake and blood pressure. There are reports of mitochondrial function, Na+-K+-ATPase and PLC/PKC pathway involved in the regulation of TRPM5 activity, whether high salt affects these factors, and thus damages TRPM5-mediated bitter taste perception needs to be confirmed. We therefore proposed a hypothesis that long-term high salt inhibiting TRPM5-mediated aversion reaction to high salt by damaging mitochondria function, Na+-K+-ATPase function and PLC/PKC pathway, which thereby causing salt taste sensitivity decreased and salt intake and blood pressure increased. Regulation of TRPM5 function can reverse the above process. This study can deepen the understanding of the mechanism of salt taste regulation, and provide new intervention strategy for the prevention and treatment of hypertension.

高盐是致高血压与卒中的重要环境因素之一，限盐是预防高血压的重要措施，盐味觉改变在调控摄盐量中起关键作用。盐摄入过多会激活苦味觉，产生"咸得发苦"的厌恶感觉，这种生理性保护机制是否受损并不清楚。我们研究发现长期高盐摄入导致苦味觉敏感性显著降低，动物模型证实盐味觉敏感性及舌上皮苦味觉受体TRPM5表达下降，且与摄盐量及血压相关。有报道线粒体功能、Na+-K+-ATPase及PLC/PKC通路参与TRPM5活性调控，但高盐是否影响了这些因素，从而损害TRPM5介导的苦味觉感知还需证实。为此，我们提出理论假设：长期高盐摄入损害线粒体、Na+-K+-ATPase功能及PLC/PKC通路，抑制TRPM5介导的对高盐的厌恶反应，使高盐味觉感知敏感性下降、盐摄入量增加及血压升高，调控TRPM5可逆转上述过程。本研究可深化对盐味觉调控机制的认识，为高血压的防治提供新的干预措施。

高盐是致高血压与卒中的重要环境因素之一，限盐是预防高血压的重要措施。盐摄入过多会激活苦味觉产生"咸得发苦"的厌恶感觉，这种生理性保护机制在高盐饮食中是否受损及其调节机制并不清楚。我们以高盐饮食对TRPM5介导的苦味觉调控机制为核心，以WT、TRPM5-/-小鼠为研究对象，在整体与离体组织、细胞水平进行研究，并在高血压及健康人群中进行临床验证，取得重要研究成果如下：.1.阐明长期高盐摄入抑制舌上皮组织PKCα表达，使PKC对TRPM5的T1052位点磷酸化作用减弱，从而降低舌上皮TRPM5的表达和功能，导致高盐产生的苦味觉厌恶-回避反应减弱，并使其介导的对伤害性高盐刺激的厌恶-回避反应减弱，进而引起盐摄入量的持续性增加，但并未改变ENaC的表达及其介导的低盐喜好性。.2.揭示长期摄入苦瓜提取物（BME）可通过抑制高盐诱导的RhoA / Rho激酶途径的过度活化，降低肌球蛋白轻链激酶和肌球蛋白磷酸酶靶向亚基1的磷酸化水平进而改善高盐诱导心肌肥大及功能异常，以及减弱L型Ca2+通道介导的平滑肌细胞Ca2+内流从而抑制血管收缩。.3.人群研究中发现高盐饮食患者对高盐味觉的敏感性显著下降，其盐喜好性及摄盐量与中枢岛叶与眶额叶脑区电活动强度显著正相关。同时在高血压及健康人群中，高盐饮食人群对苦味的敏感度降低，具有高苦味感知的受试者具有较低的盐摄入量，且其收缩压也有降低的趋势。.本项目结果发表论文4篇，其中发表1区论文1篇（Hypertension，IF：7.713），研究成果编入《高血压诊治新进展2018》及《高血压学》，项目申请人作为常务副主编参编《高血压防治：科学证据解读》进行科普宣讲，培养研究生2名。本项目阐明盐味觉感知异常在高盐摄入中的作用机制，通过增强苦味觉感知产生对高盐摄入的厌恶反应，从而达到减少摄盐量及降低血压的目的，将为长期高盐饮食人群高血压的防治提供新的干预靶点和策略。