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mTORC1 Deficiency Modifies Volume Homeostatic Responses to Dietary Sodium in a Sex-Specific Manner
Danielle L Brooks1, Amanda E Garza1, Ezgi Caliskan Guzelce1
1Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA.
Abstract:
The mechanistic target of the rapamycin (mTOR) pathway plays a role in features common to both excess salt/aldosterone and cardiovascular/renal diseases. Dietary sodium can upregulate mTORC1 signaling in cardiac and renal tissue, and the inhibition of mTOR can prevent aldosterone-associated, salt-induced hypertension. The impact of sex and age on mTOR's role in volume homeostasis and the regulation of aldosterone secretion is largely unknown. We hypothesize that both age and sex modify mTOR's interaction with volume homeostatic mechanisms. The activity of 3 volume homeostatic mechanisms-cardiovascular, renal, and hormonal (aldosterone [sodium retaining] and brain natriuretic peptide [BNP; sodium losing])-were assessed in mTORC1 deficient (Raptor+/-) and wild-type male and female littermates at 2 different ages. The mice were volume stressed by being given a liberal salt (LibS) diet. Raptor+/-mice of both sexes when they aged: (1) reduced their blood pressure, (2) increased left ventricular internal diameter during diastole, (3) decreased renal blood flow, and (4) increased mineralocorticoid receptor expression. Aldosterone levels did not differ by sex in young Raptor+/- mice. However, as they aged, compared to their littermates, aldosterone decreased in males but increased in females. Finally, given the level of Na+ intake, BNP was inappropriately suppressed, but only in Raptor+/- males. These data indicate that Raptor+/- mice, when stressed with a LibS diet, display inappropriate volume homeostatic responses, particularly with aging, and the mechanisms altered, differing by sex.
Insights
Aging and sex significantly alter the mechanistic target of rapamycin (mTOR) pathway's role in volume homeostasis. mTORC1 deficiency in aged mice led to inappropriate cardiovascular and hormonal responses to high salt intake.
Area of Science:
- Cardiovascular Biology
- Renal Physiology
- Endocrinology
Background:
- The mechanistic target of rapamycin (mTOR) pathway is implicated in salt/aldosterone-mediated cardiovascular and renal diseases.
- Dietary sodium intake activates mTORC1 signaling in cardiac and renal tissues, and mTOR inhibition can mitigate salt-induced hypertension.
- The influence of sex and age on mTOR's function in volume balance and aldosterone regulation remains unclear.
Purpose of the Study:
- To investigate how age and sex modify the interaction between the mTOR pathway and volume homeostatic mechanisms.
- To assess the impact of mTORC1 deficiency on cardiovascular, renal, and hormonal responses to volume stress.
Main Methods:
- Utilized mTORC1 deficient (Raptor+/-) and wild-type male and female mice at two different ages.
- Administered a liberal salt (LibS) diet to induce volume stress.
- Assessed cardiovascular (blood pressure, cardiac dimensions), renal (blood flow), and hormonal (aldosterone, brain natriuretic peptide [BNP]) parameters.
Main Results:
- Aged Raptor+/- mice exhibited reduced blood pressure, increased left ventricular internal diameter, and decreased renal blood flow.
- Mineralocorticoid receptor expression was elevated in aged Raptor+/- mice.
- Sex-specific alterations in aldosterone and BNP levels were observed in aged Raptor+/- mice on a high-salt diet, indicating inappropriate volume regulation.
Conclusions:
- Mice with mTORC1 deficiency display dysregulated volume homeostasis, particularly with aging, when subjected to high salt intake.
- The observed alterations in volume regulatory mechanisms are sex-dependent, highlighting the complex interplay of age, sex, and mTOR signaling.
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