Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032617 (polyuria)
 3,056 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The discovery of aquaporin-1 (AQP1) answered the long-standing biophysical question of how water specifically crosses biological membranes. In the kidney, at least seven aquaporins are expressed at distinct sites. AQP1 is extremely abundant in the proximal tubule and descending thin limb and is essential for urinary concentration. AQP2 is exclusively expressed in the principal cells of the connecting tubule and collecting duct and is the predominant vasopressin-regulated water channel. AQP3 and AQP4 are both present in the basolateral plasma membrane of collecting duct principal cells and represent exit pathways for water reabsorbed apically via AQP2. Studies in patients and transgenic mice have demonstrated that both AQP2 and AQP3 are essential for urinary concentration. Three additional aquaporins are present in the kidney. AQP6 is present in intracellular vesicles in collecting duct intercalated cells, and AQP8 is present intracellularly at low abundance in proximal tubules and collecting duct principal cells, but the physiological function of these two channels remains undefined. AQP7 is abundant in the brush border of proximal tubule cells and is likely to be involved in proximal tubule water reabsorption. Body water balance is tightly regulated by vasopressin, and multiple studies now have underscored the essential roles of AQP2 in this. Vasopressin regulates acutely the water permeability of the kidney collecting duct by trafficking of AQP2 from intracellular vesicles to the apical plasma membrane. The long-term adaptational changes in body water balance are controlled in part by regulated changes in AQP2 and AQP3 expression levels. Lack of functional AQP2 is seen in primary forms of diabetes insipidus, and reduced expression and targeting are seen in several diseases associated with urinary concentrating defects such as acquired nephrogenic diabetes insipidus, postobstructive polyuria, as well as acute and chronic renal failure. In contrast, in conditions with water retention such as severe congestive heart failure, pregnancy, and syndrome of inappropriate antidiuretic hormone secretion, both AQP2 expression levels and apical plasma membrane targetting are increased, suggesting a role for AQP2 in the development of water retention. Continued analysis of the aquaporins is providing detailed molecular insight into the fundamental physiology and pathophysiology of water balance and water balance disorders.
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PMID:Aquaporins in the kidney: from molecules to medicine. 1177 13

Aquaporins (AQP) are a family of at least ten homologous water transporting proteins in mammals that are expressed in many epithelial, endothelial and other tissues. Abnormalities in humans and mice lacking AQPs provide direct evidence for their physiological importance. Humans lacking AQP1 or AQP2 manifest polyuria with defective urinary concentrating ability and humans with mutations in MIP (AQP0) develop cataracts. Transgenic knockout mice lacking AQP1 or AQP3 are also remarkably polyuric, and knock-in mice expressing a mutant AQP2 have severe nephrogenic diabetes insipidus resulting in impaired neonatal survival. Other interesting phenotypes in AQP knockout mice include reduced pain sensation, reduced intraocular pressure, defective corneal fluid transport and impaired dietary fat processing (AQP1), dry skin (AQP3), protection from brain swelling and impaired hearing/vision (AQP4), and reduced fluid secretion by salivary and airway submucosal glands (AQP5). However, many phenotype studies were negative, such as normal airway/lung and skeletal muscle function despite AQP expression, indicating that tissue-specific aquaporin expression does not indicate physiological significance. The general paradigm from studies on transgenic mouse models of AQP deletion is that AQPs facilitate rapid near-isosmolar transepithelial fluid absorption / secretion, as well as rapid vectorial water movement driven by osmotic gradients. The transgenic mouse studies suggest that aquaporin inhibitors may have clinical indications as diuretics and in the treatment of cerebral edema, elevated intraocular pressure, and other conditions of abnormal fluid homeostasis.
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PMID:Physiological importance of aquaporin water channels. 1217 89

Senescent female WAG/Rij rats exhibit polyuria without obvious renal disease or defects in vasopressin plasma level or V(2) receptor mRNA expression. Normalization of urine flow rate by 1-desamino-8-d-arginine vasopressin (dDAVP) was investigated in these animals. Long-term dDAVP infusion into 30-mo-old rats reduced urine flow rate and increased urine osmolality to levels comparable to those in control 10-mo-old rats. The maximal urine osmolality in aging rat kidney was, however, lower than that in adult kidney, despite supramaximal administration of dDAVP. This improvement involved increased inner medullary osmolality and urea sequestration. This may result from upregulation of UT-A1, the vasopressin-regulated urea transporter, in initial inner medullary collecting duct (IMCD), but not in terminal IMCD, where UT-A1 remained low. Expression of UT-A2, which contributes to medullary urea recycling, was greatly increased. Regulation of IMCD aquaporin (AQP)-2 (AQP2) expression by dDAVP differed between adult and senescent rats: the low AQP2 abundance in senescent rats was normalized by dDAVP infusion, which also improved targeting of the channel; in adult rats, AQP2 expression was unaltered, suggesting that IMCD AQP2 expression is not regulated by dDAVP directly. Increased AQP3 expression in senescent rats may also be involved in improved urine-concentrating capacity owing to higher basolateral water and urea reabsorption capacity.
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PMID:Correction of age-related polyuria by dDAVP: molecular analysis of aquaporins and urea transporters. 1238 83

The purpose of this study was to evaluate whether hypercalcemia is associated with downregulation of renal aquaporins (AQPs), including AQP1, AQP2, phosphorylated AQP2 (p-AQP2), AQP3, and AQP4, and if this is the case, to test whether cAMP-phosphodiesterase (PDE) inhibitor treatment can prevent AQP downregulation and prevent the development of polyuria. Vitamin D-induced hypercalcemia in rats was associated with increased urine output and reduced urine osmolality, consistent with previous findings (Levi M, Peterson L, and Berl T. Kidney Int 23: 489-497, 1983). Semiquantitative immunoblotting revealed a significant reduction in the abundance of inner medullary AQP2 (52 +/- 6% of control levels), consistent with previous studies, and of AQP2, which is phosphorylated at the PKA phosphorylation consensus site serine 256 (p-AQP2; 36 +/- 8%). Moreover, AQP3 abundance was also significantly decreased (45 +/- 7 and 61 +/- 6% of control levels in inner medulla and whole kidney, respectively). Consistent with this, immunohistochemistry demonstrated reduced AQP3 immunolabeling along the entire collecting duct. AQP4 expression was not reduced. Surprisingly, total kidney AQP1 abundance was also reduced (60 +/- 6%). AQP1 expression was reduced in the cortex and outer stripe of the outer medulla (48 +/- 7%; i.e., in proximal tubules). In contrast, AQP1 levels were not changed in the inner stripe of the outer medulla or in the inner medulla (i.e., descending thin limbs and vasa recta). Treatment with the cAMP-PDE inhibitors rolipram and milrinone in combination (inhibiting PDE IV and PDE III isoenzymes) at day 2 and onward completely prevented the hypercalcemia-induced downregulation of AQP2 and AQP3 (but not AQP1) and completely prevented the development of polyuria. In conclusion, AQP3, AQP2, and p-AQP2 are downregulated and are likely to play critical roles in the development of polyuria associated with vitamin D-induced hypercalcemia. Moreover, PDE inhibitor treatment significantly prevented the reduced expression of collecting duct AQPs and prevented the development of polyuria.
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PMID:AQP3, p-AQP2, and AQP2 expression is reduced in polyuric rats with hypercalcemia: prevention by cAMP-PDE inhibitors. 1238 9

The aquaporins (AQP) are a family of small transmembrane water channels. The discovery of AQP has provided insight into molecular mechanisms underlying renal water absorption and its regulation by vasopressin. Seven types of AQP have been identified in the kidney. AQP1 has been localized in the proximal tubule and descending thin limb, while AQP2, AQP3, and AQP4 are expressed in the collecting duct. Of these isoforms, AQP2 expression and intracellular trafficking is tightly regulated by vasopressin. Decreased expression of renal AQP has been detected in several disorders associated with polyuria and impaired ability to concentrate urine, as exemplified by nephrogenic diabetes insipidus or renal failure. In contrast, increased expression of AQP is seen in conditions leading to water retention, such as congestive heart failure, liver cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion. Thus, the understanding of molecular structure and function of aquaporins may have important implications for therapy of water balance disorders.
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PMID:[Aquaporin water channels in water balance regulation in the kidney]. 1273 79

Release of bilateral ureteral obstruction (BUO) is associated with reduced expression of renal aquaporins (AQPs), polyuria, and impairment of urine-concentrating capacity. Recently, we demonstrated that 24 h of BUO is associated with increased cyclooxygenase (COX)-2 expression in the inner medulla (IM) and that selective COX-2 inhibition prevents downregulation of AQP2. In the present study, we tested the hypothesis that COX-2 activity increases in the postobstructive phase and that this increase in COX-2 activity contributes to polyuria and impaired urine-concentrating capacity. We examined the effect of the selective COX-2 inhibitor parecoxib (5 mg.kg(-1).day(-1) via osmotic minipumps) on renal functions and protein abundance of AQP2, AQP3, Na-K-2Cl cotransporter type 2 (NKCC2), and Na-K-ATPase 3 days after release of BUO. At 3 days after release of BUO, rats exhibited polyuria, dehydration and urine and IM tissue osmolality were decreased. There were inverse changes of COX-1 and COX-2 in the IM: COX-2 mRNA, protein, and activity increased, while COX-1 mRNA and protein decreased. Parecoxib reduced urine output 1 day after release of BUO, but sodium excretion and glomerular filtration rate were unchanged. Parecoxib normalized urinary PGE(2) and PGI(2) excretion and attenuated downregulation of AQP2 and AQP3, while phosphorylated AQP2 and NKCC2 remained suppressed. Parecoxib did not improve urine-concentrating capacity in response to 24 h of water deprivation. We conclude that decreased NKCC2 and collapse of the IM osmotic gradient, together with suppressed phosphorylated AQP2, are likely causes for the impaired urine-concentrating capacity and that COX-2 activity is not likely to mediate these changes in the chronic postobstructive phase after ureteral obstruction.
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PMID:COX-2 activity transiently contributes to increased water and NaCl excretion in the polyuric phase after release of ureteral obstruction. 1722 76

The effect of endotoxemia (lipopolysaccharide, 2.5 mg/kg ip) was investigated in aquaporin (AQP) 1 knockout (KO) compared with wild-type (WT) mice. At baseline, KO mice exhibited higher water intake (WI) and urine output (UO). After endotoxemia, WI and UO remained higher in the KO than WT mice, and urine osmolality was lower. The higher serum osmolality in AQP1-KO mice during endotoxemia was associated with higher AQP2 (133 +/- 8 vs. 100 +/- 3%, P < 0.01), AQP3 (140 +/- 8 vs. 100 +/- 4%, P < 0.001) and Na(+)-K(+)-2Cl(-) cotransporter type 2 (NKCC2; 152 +/- 14 vs. 100 +/- 15%, P < 0.05) expression than that in WT mice. These responses during endotoxemia in the AQP1-KO mice compared with WT were associated with lower glomerular filtration rate (GFR) (69 +/- 8 vs. 96 +/- 8 ml/min, P < 0.05) and renal blood flow (0.77 +/- 0.1 vs. 1.01 +/- 0.1 ml/min, P < 0.01). Urinary sodium excretion and fractional sodium excretion were higher in KO compared with WT mice in endotoxemia and were accompanied by more severe tubular injury. With water repletion and comparable serum osmolalities, GFR was still lower in KO (57 +/- 13 vs. 120 +/- 6 ml/min, P < 0.01) compared with WT during endotoxemia. The abundance of AQP2 and AQP3 protein in KO mice was not different from WT mice; however, NKCC2, Na(+)/H(+) exchanger type 3, and fractional sodium excretion remained higher in KO compared with WT. Thus the polyuria in AQP1-KO mice does not protect against endotoxemia-induced acute kidney injury but rather absence of AQP1 predisposed to enhanced endotoximic renal injury.
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PMID:Role of AQP1 in endotoxemia-induced acute kidney injury. 1843 89

One of the clinical alterations observed in chronic renal disease (CRD) is the impaired urine concentration, known as diabetes insipidus (DI). Tubulointerstitial fibrosis of the kidney is also a pathological finding observed in CRD and involves composition of extracellular matrix (ECM). However, an association between these two events has not been elucidated. In this study, we showed that the extracellular-to-intracellular scaffold protein integrin-linked kinase (ILK) regulates expression of tubular water channel aquaporin-2 (AQP2) and its apical membrane presence in the renal tubule. Basally, polyuria and decreased urine osmolality were present in ILK conditional-knockdown (cKD-ILK) adult mice compared with nondepleted ILK littermates. No changes were observed in arginine-vasopressin (AVP) blood levels, renal receptor (V2R), or AQP3 expression. However, tubular AQP2 was decreased in expression and apical membrane presence in cKD-ILK mice, where the canonical V2R/cAMP axis activation is still functional, but independent of the absence of ILK. Thus, cKD-ILK constitutes a nephrogenic diabetes insipidus (NDI) model. AQP2 and ILK colocalize in cultured inner medullary collecting duct (mIMCD3) cells. Specific ILK siRNAs and collagen I (Col) decrease ILK and AQP2 levels and AQP2 presence on the membrane of tubular mIMCD3 cells, which impairs the capacity of the cells to transport water under hypotonic stress. The present work points to ILK as a therapeutic target in NDI.
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PMID:Integrin-linked kinase regulates tubular aquaporin-2 content and intracellular location: a link between the extracellular matrix and water reabsorption. 2478 77

P2Y12 receptor (P2Y12-R) signaling is mediated through Gi, ultimately reducing cellular cAMP levels. Because cAMP is a central modulator of arginine vasopressin (AVP)-induced water transport in the renal collecting duct (CD), we hypothesized that if expressed in the CD, P2Y12-R may play a role in renal handling of water in health and in nephrogenic diabetes insipidus. We found P2Y12-R mRNA expression in rat kidney, and immunolocalized its protein and aquaporin-2 (AQP2) in CD principal cells. Administration of clopidogrel bisulfate, an irreversible inhibitor of P2Y12-R, significantly increased urine concentration and AQP2 protein in the kidneys of Sprague-Dawley rats. Notably, clopidogrel did not alter urine concentration in Brattleboro rats that lack AVP. Clopidogrel administration also significantly ameliorated lithium-induced polyuria, improved urine concentrating ability and AQP2 protein abundance, and reversed the lithium-induced increase in free-water excretion, without decreasing blood or kidney tissue lithium levels. Clopidogrel administration also augmented the lithium-induced increase in urinary AVP excretion and suppressed the lithium-induced increase in urinary nitrates/nitrites (nitric oxide production) and 8-isoprostane (oxidative stress). Furthermore, selective blockade of P2Y12-R by the reversible antagonist PSB-0739 in primary cultures of rat inner medullary CD cells potentiated the expression of AQP2 and AQP3 mRNA, and cAMP production induced by dDAVP (desmopressin). In conclusion, pharmacologic blockade of renal P2Y12-R increases urinary concentrating ability by augmenting the effect of AVP on the kidney and ameliorates lithium-induced NDI by potentiating the action of AVP on the CD. This strategy may offer a novel and effective therapy for lithium-induced NDI.
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PMID:P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus. 2585 80

Obstructive kidney disease is a common complication in the clinic. Downregulation of aquaporins (AQPs) in obstructed kidneys has been thought as a key factor leading to the polyuria and impairment of urine-concentrating capability after the release of kidney obstruction. The present study was to investigate the role of mitochondrial complex-1 in modulating AQPs in obstructive nephropathy. Following 7-day unilateral ureteral obstruction (UUO), AQP1, AQP2, AQP3, and vasopressin 2 (V2) receptor were remarkably reduced as determined by qRT-PCR and/or Western blotting. Notably, inhibition of mitochondrial complex-1 by rotenone markedly reversed the downregulation of AQP1, AQP2, AQP3, and V2 In contrast, AQP4 was not affected by kidney obstruction or rotenone treatment. In a separate study, rotenone also attenuated AQPs' downregulation after 48-h UUO. To study the potential mechanisms in mediating the rotenone effects on AQPs, we examined the regulation of the COX-2/microsomal prostaglandin E synthase (mPGES)-1/PGE2/EP pathway and found that COX-2, mPGES-1, and renal PGE2 content were all significantly elevated in obstructive kidneys, which was not affected by rotenone treatment. For EP receptors, EP2 and EP4 but not EP1 and EP3 were upregulated in obstructive kidneys. Importantly, rotenone strikingly suppressed EP1 and EP4 but not EP2 and EP3 receptors. However, treatment of EP1 antagonist SC-51322 could not affect AQPs' reduction in obstructed kidneys. Collectively, these findings suggested an important role of mitochondrial dysfunction in modulating AQPs and V2 receptor in obstructive nephropathy possibly via prostaglandin-independent mechanisms.
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PMID:Inhibition of mitochondrial complex-1 restores the downregulation of aquaporins in obstructive nephropathy. 2741 98


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