Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts.
Endocrinology. 2019 Apr 1;160(4):716-728. doi: 10.1210/en.2018-00989.
Both mechanistic target of rapamycin (mTOR) pathway and aldosterone are implicated in the development of cardiovascular and renal disease. However, the interaction between aldosterone and the mTOR pathway is unknown. We hypothesized the following: that (i) increased aldosterone will modulate the activity of the mTORC1 and mTORC2 molecular pathways in the heart and kidney; (ii) a physiologic increase in aldosterone will affect these pathways differently than a pathophysiologic one; and (iii) the changes in the mTOR level/activity will differ between the heart and kidney. In both kidney and heart tissues, phosphorylation of mTOR is significantly decreased when aldosterone levels are physiologically increased (by dietary sodium restriction), followed by a decrease in phosphorylated p70S6K1 in cardiac, but not renal, tissue. Sirtuin 1, an epigenetic modulator, is decreased in the heart but increased in the kidney. Conversely, pathophysiologic aldosterone levels (an infusion for 3 weeks) had divergent effects on phosphorylated mTOR and the downstream substrates of mTORC1 and mTORC2 in cardiac and renal tissues. Increased aldosterone levels significantly alter mTOR activity in the heart and kidney. In the kidney, substantial differences were noted if the increase was produced physiologically vs pathophysiologically, suggesting that mTOR activity, in part, may mediate aldosterone-induced renal damage. Thus, modulating mTOR activity may reduce aldosterone-dependent renal damage similar to mineralocorticoid receptor blockade but potentially with less adverse side effects.
雷帕霉素靶蛋白（mTOR）通路和醛固酮都与心血管和肾脏疾病的发生有关。然而，醛固酮与 mTOR 通路之间的相互作用尚不清楚。我们提出以下假设：（i）醛固酮增加将调节心脏和肾脏中 mTORC1 和 mTORC2 分子途径的活性；（ii）生理上增加醛固酮会对这些途径产生不同于病理生理的影响；（iii）mTOR 水平/活性的变化在心脏和肾脏之间会有所不同。在肾脏和心脏组织中，当醛固酮水平生理性增加（通过饮食限制钠）时，mTOR 的磷酸化显着降低，随后心脏组织中磷酸化的 p70S6K1 减少，但肾脏组织中没有减少。组蛋白去乙酰化酶 1（一种表观遗传调节剂）在心脏中减少，而在肾脏中增加。相反，病理生理醛固酮水平（输注 3 周）对心脏和肾脏组织中 mTORC1 和 mTORC2 的磷酸化 mTOR 和下游底物产生了不同的影响。醛固酮水平升高显着改变了心脏和肾脏中的 mTOR 活性。在肾脏中，如果增加是生理性的还是病理性的，则会注意到明显的差异，这表明 mTOR 活性部分可能介导醛固酮引起的肾脏损伤。因此，调节 mTOR 活性可能会减少醛固酮依赖性肾脏损伤，类似于盐皮质激素受体阻断剂，但潜在的不良反应可能更少。
