Aldosterone Modulates the Mechanistic Target of Rapamycin Signaling in Male Mice

Area of Science:

• Cardiovascular and Renal Physiology
• Molecular Signaling Pathways

Background:

• Aldosterone and the mechanistic target of rapamycin (mTOR) pathway are linked to cardiovascular and renal diseases.
• The interaction between aldosterone and the mTOR pathway remains largely unknown.

Purpose of the Study:

• To investigate how aldosterone modulates mTORC1 and mTORC2 pathway activity in the heart and kidney.
• To differentiate the effects of physiological versus pathophysiological increases in aldosterone.
• To compare changes in mTOR activity between cardiac and renal tissues.

Main Methods:

• Assessed phosphorylation of mTOR and its downstream substrates (p70S6K1) in cardiac and renal tissues.
• Measured Sirtuin 1 levels, an epigenetic modulator.
• Administered physiological (dietary sodium restriction) and pathophysiological (3-week infusion) increases in aldosterone.

Main Results:

• Physiological aldosterone increase decreased mTOR phosphorylation in both heart and kidney, with reduced p70S6K1 in the heart.
• Sirtuin 1 levels decreased in the heart but increased in the kidney under physiological conditions.
• Pathophysiological aldosterone levels induced divergent effects on mTOR signaling in cardiac versus renal tissues.

Conclusions:

• Increased aldosterone levels significantly alter mTOR activity in the heart and kidney.
• Differences in mTOR response to physiological versus pathophysiological aldosterone in the kidney suggest mTOR mediates aldosterone-induced renal damage.
• Targeting mTOR activity could offer a novel therapeutic strategy for aldosterone-dependent renal damage, potentially with improved side effect profiles compared to mineralocorticoid receptor blockade.