Molecular Mechanisms of Impaired Urinary Concentrating Ability in Glucocorticoid-Deficient Rats

Chen, Yung‐Chang; Cadnapaphornchai, Melissa A.; Summer, Sandra N.; Falk, Sandor; Li, Chunling; Wang, Weidong; Schrier, Robert W.

doi:10.1681/asn.2004110944

Cited by 35 publications

(31 citation statements)

References 31 publications

(24 reference statements)

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“…32 One postnatal study in adrenalectomized adult rats showed a decrease in mean BP and cardiac output in rats that received only mineralocorticoid replacement compared with controls that received both mineralocorticoid and GC replacement. 33 Interestingly, these same rats demonstrated an impairment in urinary concentrating ability with decreased expression of aquaporin-2 and impaired countercurrent multiplication, 33 so it is difficult to sort out the effects of GC deficiency versus volume deficiency. Overall, it is unclear whether GC increase or decrease cardiac output; they may have both effects in particular settings.…”

Section: Discussionmentioning

confidence: 99%

A Critical Role for Vascular Smooth Muscle in Acute Glucocorticoid-Induced Hypertension

Goodwin¹,

Zhang²,

Geller³

2008

Journal of the American Society of Nephrology

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Although glucocorticoid (GC)-induced hypertension has commonly been attributed to promiscuous activation of the mineralocorticoid receptor by cortisol, thereby promoting excess reabsorption of sodium and water, numerous lines of evidence indicate that this is not the only or perhaps even the primary mechanism. GC induce a number of effects on vascular smooth muscle (VSM) in vitro that may be pertinent to hypertension, but their contribution in vivo is unknown. To address this question, a mouse model with a tissue-specific knockout (KO) of the GC receptor in the VSM was created and characterized. Similar to control mice, KO mice exhibited normal baseline BP and, interestingly, showed normal circadian variation in BP. When dexamethasone was administered, however, the acute hypertensive response was markedly attenuated in KO mice, and there was a trend toward a decreased chronic hypertensive response. These data suggest that the GC receptor in VSM plays a critical role in the acute hypertensive response to GC in vivo.

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Section: Discussionmentioning

confidence: 99%

A Critical Role for Vascular Smooth Muscle in Acute Glucocorticoid-Induced Hypertension

Goodwin¹,

Zhang²,

Geller³

2008

Journal of the American Society of Nephrology

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“…Moreover, a V2 receptor antagonist has been shown in this rat model of hypothyroidism to reverse the increased AQP2 and the impaired response to an acute water load (Figure 4) (44). The hypothyroid rats also demonstrated a diminution in maximal urinary concentration which was associated with a defect in the counter-current concentrating mechanism (45). This defect was related to diminished maximal medullary osmolality and down-regulation of the cotransporter, NA-K-2Cl, which initiates the counter-current concentrating mechanism.…”

Section: Hypo-and Hyperthyroidismmentioning

confidence: 79%

“…In contrast, glucocorticoid deficiency is, if anything, mildly sodium retaining. A decrease in blood pressure, however, occurs secondary to diminished cardiac output and an impaired systemic vascular response to hypotension (53). The hyponatremia of hypopituitarism, i.e., selective glucocorticoid deficiency, can be reversed with physiological doses of hydrocortisone (54).…”

Section: Glucocorticoid Deficiency and Mineralocorticoid Deficiencymentioning

confidence: 99%

Vasopressin and Aquaporin 2 in Clinical Disorders of Water Homeostasis

Schrier

2008

Seminars in Nephrology

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The cloning of the V2 vasopressin receptor was a major advance in understanding the mechanisms involved in regulation of solute-free water excretion by arginine vasopressin (AVP) (1). Subsequently, mutations of the V2 receptor gene were found to account for approximately 85% of cases of congenital nephrogenic diabetes insipidus (2). The mechanisms whereby AVP activates the V2 receptor on the basolateral membrane of the principal cells of the collecting duct and leads to increased water permeability of the apical membrane were, however, quite perplexing. The water transport across the bilipid apical membrane of the principal cells was too fast to be due to diffusion alone. Thus, the shuttle hypothesis was proposed whereby theoretical water channels would be moved from the cytoplasm to the apical membrane of the principal cells by AVP (3). The discovery of the first water channel, aquaporin 1 (AQP1), by Agre and associates led to great excitement in the biomedical community and the awarding of the Nobel Prize in Chemistry in 2003 to Peter Agre (4). Subsequently, aquaporin 2 (AQP2) was identified by Sasaki et al. in the principal cells of the collecting duct (5). Further investigations have demonstrated that AVP is the major regulator of the AQP2 water channels (6). Activation of the V2 receptor on the principal cells of the collecting duct by AVP is associated with a cascade of events involving adenylyl cyclase-mediated cyclic AMP (Figure 1) (7) which leads to both short term and long term regulation of AQP2 (8,9). The short term regulation of AVP involves shuttling the AQP2 containing vesicles from the cytoplasm to the apical membrane. With suppression of vasopressin these apical AQP2 water channels then undergo endocytosis into the cytoplasm (3). The 5' flanking region of the AQP2 gene has a cyclic AMP response element which is involved in the long term upregulation of AQP2 protein expression by AVP (9).The discovery of non-peptide antagonists to the V2 receptor have added yet another important dimension to the understanding of total body water homeostasis (10). These V2 receptor antagonists are agents that specifically block the action of AVP in humans. The several V2 receptor antagonists presently involved in clinical studies are shown in Table 1 (11). In contrast to diuretics, which enhance urine water and electrolyte excretion, the V2 receptor antagonists increase electrolyte-free water excretion.A relative excess of total body water to cation concentration leads to hyponatremia in many clinical circumstances. In fact, hyponatremia is the most frequent electrolyte disturbance in hospitalized patients (12). V2 receptor antagonists have substantial clinical implications, since the majority of the hyponatremic states are due to the non-osmotic release of AVP (13). These V2 receptor antagonists have also been important vehicles to understand several waterPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

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“…2 Experimental glucocorticoid deficiency also exhibited impaired maximal urinary concentration, which was associated with a downregulation of AQP2. 3 The role of the excessive glucocorticoid hormone, as occurs with Cushing syndrome, is also known to be associated with alteration in body water homeostasis, but the molecular mechanisms have not been studied. It has been shown, however, that patients as well as experimental animals demonstrated polyuria in the presence of excess of glucocorticoid hormone.…”

mentioning

confidence: 99%

Downregulation of UT-A1/UT-A3 Is Associated with Urinary Concentrating Defect in Glucocorticoid-Excess State

Li¹,

Wang²,

Summer³

et al. 2008

Journal of the American Society of Nephrology

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Excessive glucocorticoid hormone, as occurs with Cushing syndrome, is known to be associated with altered body water homeostasis, but the molecular mechanisms are unknown. In this study, rats treated with daily dexamethasone (Dex) for 14 d provided a model of Cushing syndrome. Compared with control rats, Dex-treated rats demonstrated increased mean arterial pressure, urine flow rate, and urinary excretion of both sodium and urea. Dex-treated rats had increased abundance of aquaporin 1 (AQP1), AQP3, and Na-K-2Cl co-transporter proteins and a marked reduction of the urea transporters UT-A1 and UT-A3. In response to an acute water load, Dex-treated rats increased water excretion more than control rats, but both groups exhibited similar AQP2 expression. In response to fluid deprivation, Dex-treated rats demonstrated an impaired urinary concentrating capacity: Urine flow rate was higher and urine osmolality was lower than control rats despite an increase in AQP1, AQP3, and Na-K-2Cl co-transporter expression. AQP2 expression was similar between the two groups, but UT-A1 and UT-A3 were decreased and urinary urea excretion was increased in Dex-treated rats. Because Dex-treated rats ingested less food and water compared with controls, paired food and water studies were performed; these substantiated the previous results. In summary, the alterations in body water observed with glucocorticoid excess may be a result, in part, of impaired urinary concentrating capacity; downregulation of UT-A1 and UT-A3 and increased urea excretion may contribute to this impairment.

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Molecular Mechanisms of Impaired Urinary Concentrating Ability in Glucocorticoid-Deficient Rats

Cited by 35 publications

References 31 publications

A Critical Role for Vascular Smooth Muscle in Acute Glucocorticoid-Induced Hypertension

A Critical Role for Vascular Smooth Muscle in Acute Glucocorticoid-Induced Hypertension

Vasopressin and Aquaporin 2 in Clinical Disorders of Water Homeostasis

Downregulation of UT-A1/UT-A3 Is Associated with Urinary Concentrating Defect in Glucocorticoid-Excess State

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