激活肾脏近端小管TRPA1改善线粒体功能抑制钠重吸收的机制

Excessive salt intake contributes to the pathogenesis of hypertension. Promoting renal sodium excretion is one of the primary methods to attenuate hypertension. The NHE3 and Na+/K+-ATPase expressed at renal proximal tubule play a critical role in sodium and water reabsorption. Abnormal sodium transport by NHE3 and Na+/K+-ATPase is closely associated with the pathogenesis of hypertension. Mitochondrial oxidative stress results in hypertension. However, whether excessive salt intake contributes to mitochondrial oxidative stress and enhanced sodium reabsorption at renal proximal tubule is poorly understood. Our previous studies found that excessive salt intake induced hypertension and renal mitochondrial dysfunction. Cinnamaldehyde, an agonist of TRPA1 could antagonize the harmful effect of excessive salt intake. Enhanced UCP2 expression by the activation of TRP channels could improve mitochondrial function and thus inhibit pathological ROS generation in endothelium. However, whether TRPA1 activation improves mitochondrial function in a UCP2-dependent manner and thus inhibits sodium absorption at renal proximal tubule is unknown. So we plan to investigate the following hypothesis in vivo and in vitro: Excessive salt intake would damage mitochondria at renal proximal tubule and disturb sodium absorption by NHE3 and Na+/K+-ATPase, which could result in salt-induced hypertension. The activation of TRPA1 by dietary supplementation of cinnamaldehyde enhances the UCP2 expression level and thus inhibits the harmful effects of excessive salt intake. The result of this study will make further understanding the physiological role of TRPA1 and mitochondrial UCP2 in kidney and provide novel theoretical basis for prevention and treatment of salt-induced hypertension in population.

高盐摄入是导致高血压的重要环境因素之一。促进肾脏排盐是拮抗高血压的重要措施。近端小管NHE3和钠钾ATP酶在调控钠重吸收中起关键作用，其异常可导致高血压的发生。线粒体氧化应激参与高血压的发生,但高盐是否引起近端小管线粒体氧化应激增加钠重吸收尚不清楚。前期工作表明高盐可致高血压及肾脏线粒体功能损伤，而桂皮醛一种瞬时受体电位通道TRPA1的激活剂可拮抗高盐的作用。我们已证实激活瞬时受体电位通道可上调UCP2改善血管内皮线粒体功能减少ROS生成，但激活TRPA1是否也影响肾脏UCP2，改善线粒体功能并促进盐的排泄还需要证实。为此，我们拟通过体内体外实验证明以下理论假设：高盐摄入损伤近端小管线粒体功能，影响NHE3和钠钾ATP酶钠重吸收导致血压升高；桂皮醛激活近端小管TRPA1上调UCP2可抑制上述改变。本研究可深化对肾脏TRPA1和线粒体功能的认识，为高血压的防治提供新的依据和干预靶点。

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