Aldosterone Decreases UT-A1 Urea Transporter Expression via the Mineralocorticoid Receptor

Abstract

Abstract. Adrenalectomy in rats is associated with urinary concentrating and diluting defects. This study tested the effect of adrenal steroids on the UT-A1 urea transporter because it is involved in the urine-concentrating mechanism. Rats were adrenalectomized and given normal saline for 14 d, after which they received (1) vehicle, (2) aldosterone, or (3) spironolactone plus aldosterone. Adrenalectomy alone significantly increased UT-A1 protein in the inner medullary tip after 7 d, whereas aldosterone repletion reversed the effect. Spironolactone blocked the aldosterone-induced decrease in UT-A1, indicating that aldosterone was working via the mineralocorticoid receptor. For verifying that glucocorticoids downregulate UT-A1 protein through a different receptor, three groups of adrenalectomized rats were prepared: (1) vehicle, (2) adrenalectomy plus dexamethasone, and (3) adrenalectomy plus dexamethasone and spironolactone. Dexamethasone significantly reversed UT-A1 protein abundance increase in the inner medullary tip of adrenalectomized rats. When spironolactone was given with dexamethasone, it did not affect the dexamethasone-induced decrease in UT-A1. There was no significant change in serum vasopressin level, aquaporin 2, or Na ϩ -K ϩ -2Cl Ϫ co-transporter NKCC2/BSC1 protein abundances or UT-A1 mRNA abundance in any of the groups. In conclusion, either mineralocorticoids or glucocorticoids can downregulate UT-A1 protein. The decrease in UT-A1 does not require both steroid hormones, and each works through a different receptor.Adrenalectomy reduces urine-concentrating ability (1-3) but also inhibits acute water diuresis (4). Both glucocorticoids and mineralocorticoids must be administered to reverse the inhibition of acute water diuresis (4). Valtin and colleagues (4) showed that giving aldosterone to adrenalectomized rats after an acute water load corrected their diluting ability, whereas prednisolone corrected urine flow. These findings suggest that both adrenal steroids are involved in the regulation of urinary concentration and dilution.Urea plays an important role in the urine-concentrating mechanism (reviewed in (5)). We previously studied the effect of glucocorticoids (dexamethasone) on UT-A1 protein abundance in adrenalectomized rats. We showed that glucocorticoids decrease the protein abundance of the UT-A1 urea transporter in the inner medullary tip of adrenalectomized rats (6) and in conditions associated with excess glucocorticoid, such as uncontrolled diabetes (7,8). Presumably, in catabolic states in which glucocorticoid levels are increased, UT-A1 is downregulated to permit more nitrogenous waste to be excreted into the urine and to prevent excessive reabsorption of urea across the terminal inner medullary collecting duct (IMCD).The effect of mineralocorticoids (aldosterone) on UT-A1 protein abundance in adrenalectomized rats has not been studied. Ohara et al. (9) studied mineralocorticoid deficiency, induced by adrenalectomy with glucocorticoid replacement, and showed that it had no effect on ...

Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

“…Administering mineralocorticoids to adrenalectomized rats also decreases UT-A1 protein abundance in the inner medulla (41). This decrease can be blocked by spironolactone, a mineralocorticoid receptor antagonist (41).…”

“…This decrease can be blocked by spironolactone, a mineralocorticoid receptor antagonist (41). Both mineralocorticoid and glucocorticoid hormones appear to work through their respective receptors because spironolactone does not block the decrease due to dexamethasone (41).…”

Renal Phenotype of UT-A Urea Transporter Knockout Mice

“…For example, the downregulation of collecting duct urea transporters seen in extracellular fluid volume expanded states (30) could be viewed as a homeostatic response that could increase water and salt excretion. Furthermore, some of the effects of glucocorticoids on water balance could be a consequence of the effect of glucocorticoids to down-regulate urea transporter expression in the IMCD (31,32).…”

Effect of osmotic stress on expression of a putative facilitative urea transporter in the kidney and urinary bladder of the marine toad,Bufo marinus

“…The renal urea transporter UT-A has four isoforms: UT-A1 (Shayakul et al, 1996), UT-A2 (Smith et al, 1995), UT-A3 (Karakashian et al, 1999) and UT-A4 (Karakashian et al, 1999). Mammalian UTAs are expressed in the renal medulla of the kidney and stimulated by several hormones such as arginine-vasopressin (AVP), glucocorticoids and mineralocorticoids (Wade et al, 2000;Shayakul et al, 2000;Peng et al, 2002;Gertner et al, 2004), and also in various physiological and pathological states (Shayakul et al, 2000;Sands, 2004).…”