Aims High 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 results In 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 increased Crh and Pomc mRNA 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, Fkbp5 mRNA 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 of Tonebp and Avpr1b in the anterior pituitary suggested that vasopressin signalling contributes to hypothalamic–pituitary–adrenal axis activation by high salt diet. Conclusion Chronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells.

High salt intake is common and contributes to poor cardiovascular health. Sustained cortisol excess also induces an adverse cardiovascular profile. Urinary cortisol excretion positively correlates with urinary sodium excretion. We hypothesised that this was due to hypothalamic-pituitary-adrenal axis activation by high salt intake.In male C57BL6/J mice, 2 weeks of high salt intake increased Crh and Pomc mRNA abundance in the hypothalamus and anterior pituitary, respectively and caused a sustained rise in plasma corticosterone. Plasma copeptin and anterior pituitary V1b receptor mRNA expression was elevated, which may contribute to basal HPA axis activation. Additionally, high salt intake amplified glucocorticoid response to restraint stress, indicative of enhanced HPA axis sensitivity. In the periphery, high salt intake reduced the binding capacity of corticosteroid-binding globulin, enhancing glucocorticoid bioavailability. Within several tissues, the expression of glucocorticoid-regenerating enzyme, 11β-hydroxysteroid dehydrogenase type 1, was increased and the glucocorticoid receptor downregulated. Overall, high salt intake increased glucocorticoid exposure in the hippocampus, anterior pituitary and liver.Chronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells. This shows direct connectivity between salt homeostasis and HPA axis function. The cumulative effect is likely maladaptive and may contribute to the long-term health consequences of a high salt diet.

Cutaneous wound healing typically results in scarring; however, chronic wounds (CWs) represent a global and escalating health burden causing substantial morbidity and mortality. Estimated to cost Medicare up to $96.8 billion pa and with a profound paucity of effective therapeutics, novel interventions to improve healing are urgently needed. In this study, we assess the impact of manipulating the melanocortin 1 receptor (MC1R) on acute wound healing using a selective agonist, BMS-470539 (MC1R-Ag). MC1R agonism resulted in accelerated wound closure and reepithelialisation in wildtype but not MC1Re/e mice, which harbour a non-functional receptor. MC1R-Ag improved wound perfusion and lymphatic drainage by promoting angiogenesis and lymphangiogenesis, reducing local oxidative stress and inflammation with a knock-on effect of reduced scarring. To assess whether manipulating MC1R would be of benefit in pathological healing, we developed a novel murine model of chronic cutaneous wounds. By combining advanced age and locally elevated oxidative stress, factors shown to be present in most human CWs regardless of their category, resultant wounds expand 5-fold into the surrounding tissue, produce exudate and generate slough. Histological comparisons to human CWs demonstrate robust recapitulation of the hallmarks of human disease, including hyperproliferative epidermis, fibrinous exudate and vasculitis. Crucially, our model facilitates the in vivo study of candidate therapies to rescue derailed healing responses. We have identified that abrogation of MC1R signalling, using MC1Re/e mice, exacerbates CWs with enhanced exudate and NETosis. In contrast, topical administration of an MC1R agonist following ulcer debridement rescues the healing response, highlighting MC1R agonism as a candidate therapeutic approach for human CWs. We anticipate that our unique model will become a valuable tool to elucidate mechanisms of ulcer development and persistence.

Loss‐of‐function mutations in Hsd11b2, the gene encoding the cortisol‐metabolising enzyme 11βHSD2, causes the hypertensive syndrome of Apparent Mineralocorticoid Excess. In affected individuals, overactivation of the mineralocorticoid receptor by cortisol is causative. Hypertension is salt‐sensitive, attributed to enhanced sodium reabsorption in the distal nephron and renal sodium retention. However, in the brain, 11βHSD2‐expressing neurons regulate salt appetite. We previously generated mice with conditional knockout of Hsd11b2 in the brain (Hsd11b2.BKO), which displayed enhanced salt preference and salt‐sensitive hypertension (DOI: 10.1161/CIRCULATIONAHA.115.019341). The mechanisms of salt‐sensitivity are unknown. In the current study we examined renal artery vasoreactivity and the in vivo acute pressure natriuresis response in male Hsd11b2.BKO mice and control littermates. Mice (n=10 per genotype/diet) were fed either high salt (3% Na) or 0.3% Na diet for 7 days. Animals were humanely killed, the renal arteries were isolated and mounted on a wire‐myograph to generate cumulative concentration‐response curves to phenylephrine and the nitric oxide donor, sodium nitroprusside. High salt diet significantly increased the sensitivity of the renal artery to phenylephrine‐induced vasoconstriction in Hsd11b2.BKO mice (LogEC50 0.3% diet ‐6.41±0.07 vs high salt ‐6.91±0.11; p=0.0013) but not in control mice. Sodium nitroprusside induced concentration‐dependent relaxation of renal arteries: the maximum relaxation was significantly reduced from 88±3% to 65±4% in Hsd11b2.BKO after high salt feeding (p<0.01); this was not seen in control mice. In other experiments, mice (n=5‐7 per genotype/diet) were anesthetised (thiobutabarbital sodium, 120mg/kg IP) and fractional renal sodium excretion was measured at baseline and following acutely increased blood pressure, achieved by sequential arterial ligation. In all mice, sodium excretion increased with blood pressure. In the high salt group, the pressure natriuresis response was significantly attenuated in Hsd11b2.BKO mice, compared to control animals. We find that genetic amplification of mineralocorticoid signalling in the brain attenuates the normal renal vascular and tubular adaptation to high salt intake. This regulation of renal salt excretion by the central nervous system may have implications for salt‐sensitive hypertension in humans.