Vasopressin increases Na-K-2Cl cotransporter expression in thick ascending limb of Henle’s loop

Kim, Gheun-Ho; Ecelbarger, Carolyn A.; Mitchell, Carter A.; Packer, Randall K.; Wade, James B.; Knepper, Mark A.

doi:10.1152/ajprenal.1999.276.1.f96

Cited by 209 publications

(257 citation statements)

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“…Thus, a diminution in this transporter protein could diminish medullary osmolality and thereby impair maximal urinary concentration. In the rat, AVP is known to upregulate the Na-K-2Cl co-transporter expression in the thick ascending limb (17). However, as already noted, in the present study plasma AVP concentrations were comparable in the hypothyroid and euthyroid animals.…”

Section: Discussionsupporting

confidence: 56%

Urinary Concentrating Defect in Hypothyroid Rats

Cadnapaphornchai¹,

Kim²,

Gurevich³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Hypothyroidism is associated with impaired urinary concentrating ability in humans and animals. The purpose of this study was to examine protein expression of renal sodium chloride and urea transporters and aquaporins in hypothyroid rats (HT) with diminished urinary concentration as compared with euthyroid controls (CTL) and hypothyroid rats replaced with L-thyroxine (HTϩT). Hypothyroidism was induced by aminotriazole administration. Body weight, water intake, urine output, solute and urea excretion, serum and urine osmolality, serum creatinine, 24-h creatinine clearance, and fractional excretion of sodium were comparable among the three groups. However, with 36 h of water deprivation, HT rats demonstrated significantly greater urine flow rates and decreased urine and medullary osmolality as compared with CTL and HTϩT rats at comparable plasma vasopressin concentrations. Western blot analyses revealed decreased renal protein abundance of transporters, including Na-K-2Cl, Na-K-ATPase, and NHE3, in HT rats as compared with CTL and HTϩT rats. Protein abundance of renal AQP1 and urea transporters UTA 1 and UTA 2 did not differ significantly among study groups. There was however a significant decrease in protein abundance of AQP2, AQP3, and AQP4 in HT rats as compared with CTL and HTϩT rats. These findings demonstrate a decrease in the medullary osmotic gradient secondary to impaired countercurrent multiplication and downregulation of aquaporins 2, 3, and 4 as contributors to the urinary concentrating defect in the hypothyroid rat.Hypothyroidism is a very common clinical disorder that is associated with abnormalities in many organs, including the kidney. The ability to conserve water during periods of fluid deprivation is an important function of the kidney. Hypothyroidism has been associated with an impaired urinary concentrating capacity (1,2). However, the mechanisms of this defect at the cellular and molecular level have not been defined.In the present study, the effect of hypothyroidism in rats on the pivotal components of the urinary concentrating mechanism have been examined and compared with euthyroid animals. These components during fluid deprivation include release of the antidiuretic hormone, arginine vasopressin (AVP), and upregulation of the abundance of aquaporin-2 (AQP2) water channels in the principal cells of the collecting duct. Activation of the countercurrent concentrating mechanism, which is initiated by increased sodium-potassium-2 chloride (Na-K-2Cl) co-transporter in the water impermeable ascending limb, creates the osmotic driving force for passive water reabsorption across the collecting duct. There are also roles for other water channels, including aquaporins 1, 3, and 4, and for urea transporters in urinary concentration. The present study was undertaken to define the effect of hypothyroidism on these various molecular events during fluid deprivation in the rat. Materials and Methods Animal ModelThe study protocol was approved by the University of Colorado Institutional Animal Ca...

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Section: Discussionsupporting

confidence: 56%

Urinary Concentrating Defect in Hypothyroid Rats

Cadnapaphornchai¹,

Kim²,

Gurevich³

et al. 2003

Journal of the American Society of Nephrology

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“…Measuring vasopressin levels in rats can be problematic because any factor that causes the rat to become anxious can result in a large and rapid release of vasopressin from the posterior pituitary. Therefore, we also measured the protein abundance of AQP2 and NKCC2/BSC1, two proteins whose abundances are increased by vasopressin (20,21), but we found no significant difference in either AQP2 or NKCC2/ BSC1 protein abundance. Therefore, it seems that changes in vasopressin levels did not contribute to the aldosterone-induced decrease in UT-A1 protein abundance.…”

Section: Discussionmentioning

confidence: 74%

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

Gertner¹,

Klein²,

Bailey³

et al. 2004

Journal of the American Society of Nephrology

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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 ...

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“…An increase in the abundance of the bumetamide-sensitive Na-K-2Cl cotransporter protein in the thick ascending limb has been observed in the rat kidney in response to either chronic water restriction or chronic infusion of a vasopressin V2 receptor agonist (Kim et al, 1999). However, this direct effect of vasopressin on the reabsorption of sodium in the thick ascending limb occurs only in some rodents.…”

Section: Renal Consequences Of a High Level Of Vasopressin In A Healtmentioning

confidence: 99%

Mild dehydration, vasopressin and the kidney: animal and human studies

Bouby

Fernandes

2003

Eur J Clin Nutr

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Water balance depends essentially on fluid intake and urine excretion. Mild dehydration and the consequent hypertonicity of the extracellular fluid induce an increase in vasopressin secretion, thus stimulating urine concentrating processes and the feeling of thirst. The osmotic threshold for the release of vasopressin is lower than that for thirst and also shows appreciable individual variation. Sustained high levels of vasopressin and low hydration induce morphological and functional changes in the kidney. However, they could also be risk factors in several renal disorders, such as chronic renal failure, diabetic nephropathy and saltsensitive hypertension.

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Vasopressin increases Na-K-2Cl cotransporter expression in thick ascending limb of Henle’s loop

Cited by 209 publications

References 21 publications

Urinary Concentrating Defect in Hypothyroid Rats

Urinary Concentrating Defect in Hypothyroid Rats

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

Mild dehydration, vasopressin and the kidney: animal and human studies

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