Mineralocorticoid and Glucocorticoid Receptors Stimulate Epithelial Sodium Channel Activity in a Mouse Model of Cushing Syndrome

Abstract

Abstract-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 g/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 ␣1 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.

Regulation of epithelial Na+channels by adrenal steroids: mineralocorticoid and glucocorticoid effects

“…Increased levels of NHE3 mRNA (6) and protein (24) were reported previously. The effects on NKCC2 were more surprising, since increasing glucocorticoid levels through ACTH treatment decreased renal levels of mRNA for this transporter (4). The increases in expression of NCC were the largest of the three (1.7-fold).…”

High-dose spironolactone changes renin and aldosterone levels in acutely decompensated heart failure

“…Activation of the RAAS causes reabsorption of Na + and the excretion of K + in various epithelia such as the distal nephron [29]. Higher renin and aldosterone levels at admission were also associated with lower urinary Na/K ratio levels; these findings were not reproduced when patients were submitted to MRA.…”

In vivo nuclear translocation of mineralocorticoid and glucocorticoid receptors in rat kidney: differential effect of corticosteroids along the distal tubule

“…Using a set of experiments in intact rats on different sodium intakes and in ADX rats treated with different corticosterone replacement doses, we provide evi- The DCT begins at the end of the TAL (T) and is characterized along its entire length by the expression of the NCC. The early DCT (1) and the late DCT (2) can be distinguished based on the different expression levels of 11␤-HSD2 and CB, which are low in early DCT (1) and are high in late DCT (2). The GR is highly abundant in the cell nuclei of proximal tubules (P), TAL (T), and early DCT (1), but vanishes along the late DCT (2) in parallel with the increasing 11␤-HSD2 levels.…”

“…Geering and coworkers (22) were the first to suggest that the occupancy of both receptors is necessary to achieve a full biological response. Although there is evidence for some functional compensation of the GR in MRϪ/Ϫ mice (48), both receptors appear to be important for the control of sodium transport in the ASDN, as indicated by recent findings in mouse models with targeted inactivation of the MR in the renal collecting system (46), overexpression of the GR in the collecting duct (42), or with pharmacological inhibition of either the MR or the GR in ACTH-induced Cushing's syndrome (2). Based on recent experiments in a mouse collecting duct cell line, Gaeggeler and coworkers (19) came up with the idea that the exclusive occupancy of MR provides a limited increase in sodium transport which is adequate for (circadian) maintenance requirements under low plasma aldosterone levels, while occupancy of both receptors would lead to the maximal response needed for maximum sodium retention under severe salt restriction and/or stress.…”