AbstractAimsHigh salt intake is common and contributes to poor cardiovascular health. Urinary sodium excretion correlates directly with glucocorticoid excretion in humans and experimental animals. We hypothesized that high salt intake activates the hypothalamic–pituitary–adrenal axis activation and leads to sustained glucocorticoid excess.Methods and resultsIn male C57BL/6 mice, high salt intake for 2–8 weeks caused an increase in diurnal peak levels of plasma corticosterone. After 2 weeks, high salt increasedCrhandPomcmRNA abundance in the hypothalamus and anterior pituitary, consistent with basal hypothalamic–pituitary–adrenal axis activation. Additionally, high salt intake amplified glucocorticoid response to restraint stress, indicative of enhanced axis sensitivity. The binding capacity of Corticosteroid-Binding Globulin was reduced and its encoding mRNA downregulated in the liver. In the hippocampus and anterior pituitary,Fkbp5mRNA levels were increased, indicating increased glucocorticoid exposure. The mRNA expression of the glucocorticoid-regenerating enzyme, 11β-hydroxysteroid dehydrogenase Type 1, was increased in these brain areas and in the liver. Sustained high salt intake activated a water conservation response by the kidney, increasing plasma levels of the vasopressin surrogate, copeptin. Increased mRNA abundance ofTonebpandAvpr1bin the anterior pituitary suggested that vasopressin signalling contributes to hypothalamic–pituitary–adrenal axis activation by high salt diet.ConclusionChronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells.