Final hormone in this cascade. This antinatriuretic factor is essential for

Final hormone in this cascade. This antinatriuretic factor is essential for proper Na+ balance (5, 6). Decreases in blood pressure evoke via renin?AngII signaling secretion of aldosterone from the adrenal gland. Aldosterone through the mineralocorticoid receptor (MR) stimulates ENaC in the ASDN to minimize renal sodium excretion in protection of Na+ balance and vascular volume (2, 4). Pathological increases in aldosterone elevate blood pressure by promoting inappropriate renal sodium retention (7, 8). Inhibition of ENaC ameliorates inappropriate renal sodium retention. In contrast, pathological decreases in aldosterone result in sodium wasting arising from inappropriate increases in renal sodium excretion (4, 8, 9). MR agonism and antagonism increase and decrease ENaC activity, respectively (10?2). There is strong support for a tight positive relation between the levels and actions of aldosterone and ENaC activity, sodium balance, and blood pressure.RKey aspects of these relations, however, remain obscure. For instance, whereas the temporal coupling between changes in blood pressure and sodium excretion is tight, pressure-induced changes in circulating aldosterone are comparatively slow. Moreover, residual but significant ENaC RRx-001 web activity is present in the ASDN of MR knockout mice (13), and, in some instances, ENaC activity is high in the absence of significant changes in aldosterone (12). Findings such as these suggest that, although aldosterone is capable of increasing ENaC activity, its absence is less effective at decreasing it. Several hormones and paracrine factors, in addition to aldosterone, modulate the activity of ENaC. For instance, vasopressin (AVP) decreases renal sodium excretion by increasing the activity of ENaC and sodium reabsorption in the ASDN in parallel with aldosterone (14?6). Such observations suggest that aldosterone serves as one of many factors modulating ENaC activity, rather than functioning as a requisite master regulator of the channel. Here we ask whether aldosterone is an absolute requirement for ENaC activity, testing the necessity and sufficiency of this hormone for channel expression and activity in the ASDN. We find that ENaC is expressed and active in the absence of aldosterone. Adrenal insufficiency elevates plasma AVP concentration. AVP stimulates ENaC in adrenalectomized (Adx) mice through a posttranslational mechanism via V2 receptors. Thus, although aldosterone is sufficient to stimulate ENaC activity in the ASDN, it is not necessary for activity, and ENaC activity in the ASDN can be high in the absence of this and other corticosteroids. These findings provide important insights about the role of ENaC and its regulation in pathological states of hyponatremia, such as that during adrenal insufficiency. ResultsENaC Is Expressed and Active in the ASDN of Adx Mice. We tested the necessity of adrenal steroids, including mineralocorticoids, to the expression and activity of ENaC in principal cells by assaying directly the activity of this channel with patch-clamp electrophysiology in split-open ASDN isolated from Adx mice. As expected, adrenalectomy significantly decreased plasma (��)-Zanubrutinib clinical trials corticosterone levels to the lower limit of quantification, and it significantly increased plasma [K+], and decreased plasma osmolality and body weight (Fig. S1). Surprisingly, ENaC expression and activity were robust in ASDN from Adx mice. Fig. 1 (see also Table 1) shows typical single-channel current traces from cell-Author c.Final hormone in this cascade. This antinatriuretic factor is essential for proper Na+ balance (5, 6). Decreases in blood pressure evoke via renin?AngII signaling secretion of aldosterone from the adrenal gland. Aldosterone through the mineralocorticoid receptor (MR) stimulates ENaC in the ASDN to minimize renal sodium excretion in protection of Na+ balance and vascular volume (2, 4). Pathological increases in aldosterone elevate blood pressure by promoting inappropriate renal sodium retention (7, 8). Inhibition of ENaC ameliorates inappropriate renal sodium retention. In contrast, pathological decreases in aldosterone result in sodium wasting arising from inappropriate increases in renal sodium excretion (4, 8, 9). MR agonism and antagonism increase and decrease ENaC activity, respectively (10?2). There is strong support for a tight positive relation between the levels and actions of aldosterone and ENaC activity, sodium balance, and blood pressure.RKey aspects of these relations, however, remain obscure. For instance, whereas the temporal coupling between changes in blood pressure and sodium excretion is tight, pressure-induced changes in circulating aldosterone are comparatively slow. Moreover, residual but significant ENaC activity is present in the ASDN of MR knockout mice (13), and, in some instances, ENaC activity is high in the absence of significant changes in aldosterone (12). Findings such as these suggest that, although aldosterone is capable of increasing ENaC activity, its absence is less effective at decreasing it. Several hormones and paracrine factors, in addition to aldosterone, modulate the activity of ENaC. For instance, vasopressin (AVP) decreases renal sodium excretion by increasing the activity of ENaC and sodium reabsorption in the ASDN in parallel with aldosterone (14?6). Such observations suggest that aldosterone serves as one of many factors modulating ENaC activity, rather than functioning as a requisite master regulator of the channel. Here we ask whether aldosterone is an absolute requirement for ENaC activity, testing the necessity and sufficiency of this hormone for channel expression and activity in the ASDN. We find that ENaC is expressed and active in the absence of aldosterone. Adrenal insufficiency elevates plasma AVP concentration. AVP stimulates ENaC in adrenalectomized (Adx) mice through a posttranslational mechanism via V2 receptors. Thus, although aldosterone is sufficient to stimulate ENaC activity in the ASDN, it is not necessary for activity, and ENaC activity in the ASDN can be high in the absence of this and other corticosteroids. These findings provide important insights about the role of ENaC and its regulation in pathological states of hyponatremia, such as that during adrenal insufficiency. ResultsENaC Is Expressed and Active in the ASDN of Adx Mice. We tested the necessity of adrenal steroids, including mineralocorticoids, to the expression and activity of ENaC in principal cells by assaying directly the activity of this channel with patch-clamp electrophysiology in split-open ASDN isolated from Adx mice. As expected, adrenalectomy significantly decreased plasma corticosterone levels to the lower limit of quantification, and it significantly increased plasma [K+], and decreased plasma osmolality and body weight (Fig. S1). Surprisingly, ENaC expression and activity were robust in ASDN from Adx mice. Fig. 1 (see also Table 1) shows typical single-channel current traces from cell-Author c.

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