mTORC1 Deficiency Modifies Volume Homeostatic Responses to Dietary Sodium in a Sex-Specific Manner

Mechanistic target of 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 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 three volume homeostatic mechanisms---cardiovascular, renal and hormonal (aldosterone- sodium retaining and brain natriuretic peptide (BNP)- sodium losing)---were assessed in mTORC1 deficient (Raptor +/-) and wildtype male and female littermates at two different ages. The mice were volume stressed by giving 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, differ by sex.