Mineralocorticoid and glucocorticoid receptors stimulate epithelial sodium channel activity in a mouse model of Cushing syndrome.
Experiments in Cushing patients and healthy control subjects receiving adrenocorticotropic hormone (ACTH) indicate that transient renal sodium retention may contribute to the generation of hypertension. Here we have investigated the effect of chronic ACTH infusion on renal sodium handling in adult male C57BL/6J mice using selective antagonists to dissect mineralocorticoid and glucocorticoid receptor-mediated pathways. Mice were infused via osmotic minipump with ACTH (2.5 microg/d) or saline for 2 weeks before being anesthetized for renal function experiments. ACTH caused an increase in blood pressure and a reduction in fractional sodium excretion associated with enhanced activity of the epithelial sodium channel. Given separately, spironolactone and RU38486 blunted the pressor response to ACTH and the increased epithelial sodium channel activity; combined mineralocorticoid and glucocorticoid receptor blockade was required to resolve the response to ACTH excess. Dietary sodium depletion also prevented ACTH-induced hypertension. The effect of increased sodium reabsorption in the distal nephron is offset by downregulation of Na-K-Cl cotransport in the loop of Henle. Sodium excretion is normalized chronically, but blood pressure remains high; acute blockade of V1 receptors and alpha1 adrenoceptors in combination restored blood pressure to control values. In summary, ACTH excess promotes renal sodium reabsorption, contributing to the increased blood pressure; both glucocorticoid and mineralocorticoid receptor pathways are involved. These data are relevant to conditions associated with overactivity of the hypothalamic-pituitary-adrenal axis, such as obesity and chronic stress.
Bailey
Matthew A
MA
Molecular Physiology Group, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom. matthew.bailey@ed.ac.uk
Mullins
John J
JJ
Kenyon
Christopher J
CJ
D000324:Adrenocorticotropic Hormone / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003480:Cushing Syndrome / Q000378:metabolism*; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D008138:Loop of Henle / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology
D053503:Epithelial Sodium Channels; D006727:Hormone Antagonists; D000451:Mineralocorticoid Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D017483:Receptors, Vasopressin; D028021:Sodium-Potassium-Chloride Symporters; D013148:Spironolactone; D015735:Mifepristone; D000324:Adrenocorticotropic Hormone; D012964:Sodium