Abstract
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.