Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several aquaporin-type water channels are expressed in mammalian kidney and lung: AQP1 in lung microvessels and kidney proximal tubule, thin descending limb of Henle, and vasa recta; AQP2 in apical membrane of collecting duct epithelium; AQP3 and AQP4 in basolateral membranes of airway and collecting duct epithelium; and AQP5 in alveolar epithelium. Novel quantitative fluorescence methods demonstrated very high water permeabilities of the alveolar epithelial and endothelial barriers, and moderately high water permeability across distal airways. In the kidney, water permeability is high in proximal tubule and thin descending limb of Henle, and regulated by vasopressin in collecting duct. The author's laboratory has studied the role of aquaporins in organ physiology using transgenic knockout mice lacking specific aquaporins. AQP1 null mice are mildly growth-retarded, manifest a severe urinary concentrating defect, and have reduced water permeability between airspace and capillary compartments. AQP4 null mice appear normal grossly except for a mild defect in maximum urinary concentrating ability. AQP2-deficient humans have hereditary non-X-linked nephrogenic diabetes insipidus (NDI). In transfected mammalian cells, many NDI-causing AQP2 mutants are retained in the endoplasmic reticulum. The author's laboratory has found that "chemical chaperones," that is, small compounds that promote protein folding in vitro, are able to correct defective AQP2 trafficking in cell culture models. The transgenic mouse and mammalian cell models are thus beginning to provide clues about the role of aquaporins in normal physiology and disease.
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PMID:Role of aquaporin water channels in kidney and lung. 982 13

In the renal collecting duct, vasopressin acutely activates cAMP production, resulting in trafficking of aquaporin-2 water channels (AQP2) to the apical plasma membrane, thereby increasing water permeability. This acute response is modulated by long-term changes in AQP2 expression. Recently, a cAMP-responsive element has been identified in the AQP2 gene, raising the possibility that changes in cAMP levels may control AQP2 expression. To investigate this possibility, we determined AQP2 protein levels in a strain of mice, DI +/+ severe (DI), which have genetically high levels of cAMP-phosphodiesterase activity, and hence low cellular cAMP levels, and severe polyuria. Semiquantitative immunoblotting of membrane fractions prepared from whole kidneys revealed that AQP2 levels in DI mice were only 26 +/- 7% (+/-SE) of those in control mice (n = 10, P < 0.01). In addition, semiquantitative Northern blotting revealed a significantly lower AQP2 mRNA expression in kidneys from DI mice compared with control mice (43 +/- 6% vs. 100 +/- 10%; n = 6 in each group, P < 0.05). AQP3 levels were also reduced. The mice were polyuric and urine osmolalities were accordingly substantially lower in the DI mice than in controls (496 +/- 53 vs. 1,696 +/- 105 mosmol/kgH2O, respectively). Moreover, there was a linear correlation between urine osmolalities and AQP2 levels (P < 0.05). Immunoelectron microscopy confirmed the markedly lower expression of AQP2 in collecting duct principal cells in kidneys of DI mice and, furthermore, demonstrated that AQP2 was almost completely absent from the apical plasma membrane. Thus expression of AQP2 and AQP2 trafficking were severely impaired in DI mice. These results are consistent with the view that in vivo regulation of AQP2 expression by vasopressin is mediated by cAMP.
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PMID:Low aquaporin-2 levels in polyuric DI +/+ severe mice with constitutively high cAMP-phosphodiesterase activity. 995 Sep 48

The discovery of aquaporin membrane water channels by Agre and coworkers answered a long-standing biophysical question of how water specifically crosses biologic membranes, and provided insight, at the molecular level, into the fundamental physiology of water balance and the pathophysiology of water balance disorders. Of nine aquaporin isoforms, at least six are known to be present in the kidney at distinct sites along the nephron and collecting duct. Aquaporin-1 (AQP1) is extremely abundant in the proximal tubule and descending thin limb, where it appears to provide the chief route for proximal nephron water reabsorption. AQP2 is abundant in the collecting duct principal cells and is the chief target for vasopressin to regulate collecting duct water reabsorption. Acute regulation involves vasopressin-regulated trafficking of AQP2 between an intracellular reservoir and the apical plasma membrane. In addition, AQP2 is involved in chronic/adaptational regulation of body water balance achieved through regulation of AQP2 expression. Importantly, multiple studies have now identified a critical role of AQP2 in several inherited and acquired water balance disorders. This concerns inherited forms of nephrogenic diabetes insipidus and several, much more common acquired types of nephrogenic diabetes insipidus where AQP2 expression and/or targeting are affected. Conversely, AQP2 expression and targeting appear to be increased in some conditions with water retention such as pregnancy and congestive heart failure. AQP3 and AQP4 are basolateral water channels located in the kidney collecting duct, and AQP6 and AQP7 appear to be expressed at lower abundance at several sites including the proximal tubule. This review focuses mainly on the role of AQP2 in water balance regulation and in the pathophysiology of water balance disorders.
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PMID:Physiology and pathophysiology of renal aquaporins. 1007 16

Three aquaporins (AQP) are present in the membrane of the principal collecting duct cells. On the apical side, the levels of AQP2 protein are increased in response to both arginine vasopressin and water deprivation. However, whether this change parallels changes in the abundance of AQP3 and AQP4 in the basolateral membrane is less well known. This study evaluates the effect of either dehydration or water loading on the rat kidney mRNA expression of AQP2, AQP3, and AQP4. Poly(A+)RNA was prepared from renal cortex and medulla of control, water-deprived, well hydrated, and water-deprived rats treated with OPC31260, a V2 receptor antagonist. Northern blots were done and mRNA levels were quantified using a PhosphorImager system. Relative to control, water deprivation increased the expression of cortical AQP2, -3, and -4, whereas water loading decreased the cortical and medullar expression of AQP2, -3, and -4. Therefore, in addition to AQP2 and -3, AQP4 expression is also regulated by water intake. Treatment with OPC31260 (40 mg/kg of weight per d) inhibited up to 20 to 30% the upregulation of AQP-mRNA induced by water deprivation. Blood values of arginine vasopressin and aldosterone were significantly increased by water deprivation, whereas they were unchanged by water overloading. Taken together, these results indicate that renal AQP2, -3, and -4 expression is regulated in a coordinated manner. Simultaneous up- or downregulation of the three transcripts occurred upon either water deprivation or water loading of animals, respectively. However, the signaling mechanism for the two long-term adaptive processes may be different, and, in addition to arginine vasopressin, other factors may be involved in the transcriptional regulatory processes.
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PMID:Regulation of aquaporin mRNA expression in rat kidney by water intake. 1020 52

Several aquaporin-type water channels are expressed in kidney: AQP1 in the proximal tubule, thin descending limb of Henle, and vasa recta; AQP2, AQP3, and AQP4 in the collecting duct; AQP6 in the papilla; and AQP7 in the proximal tubule. AQP2 is the vasopressin-regulated water channel that is important in hereditary and acquired diseases affecting urine-concentrating ability. It has been difficult to establish the roles of the other aquaporins in renal physiology because suitable aquaporin inhibitors are not available. One approach to the problem has been to generate and analyze transgenic knockout mice in which individual aquaporins have been selectively deleted by targeted gene disruption. Phenotype analysis of kidney and extrarenal function in knockout mice has been very informative in defining the role of aquaporins in organ physiology and addressing basic questions regarding the route of transepithelial water transport and the mechanism of near iso-osmolar fluid reabsorption. This article describes new renal physiologic insights revealed by phenotype analysis of aquaporin-knockout mice and the prospects for further basic and clinical developments.
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PMID:Lessons on renal physiology from transgenic mice lacking aquaporin water channels. 1023

We examined the effect of temporary renal ischemia (30 min or 60 min) and reperfusion (1 day or 5 days) on the expression of renal aquaporins (AQPs) and urinary concentration in rats with bilateral ischemia-induced acute renal failure (ARF). Next, we tested whether reducing ischemia/reperfusion (I/R) injury by treatment with alpha-melanocyte stimulating hormone (alpha-MSH) affects the expression of AQPs and urine output. Rats with ARF showed significant renal insufficiency, and urinary concentration was markedly impaired. In rats with mild ischemic injury (30 min), urine output increased significantly to a maximum at 48 h, and then nearly normalized within 5 days. Consistent with this, semiquantitative immunoblotting revealed that kidney AQP1 and AQP2 abundance was significantly decreased after 24 h to 30 +/- 5% and 40 +/- 11% (n = 8) of controls (n = 9), respectively (P < 0.05). Five days after ischemia, AQP2 abundance was not significantly decreased and urine output was normalized. In contrast, severe ischemic injury (60 min) resulted in a marked reduction in urine output at 24 h, despite a significant decrease in urine osmolality and solute-free water reabsorption, T(c)H(2)O. AQP1 and AQP2 abundance was markedly decreased to 51 +/- 5% and 31 +/- 9% (n = 10) of controls (n = 8) at 24 h (P < 0.05). After 5 days, the rats developed gradually severe polyuria and had very low AQP2 and AQP1 levels [11 +/- 4% and 6 +/- 2% (n = 5) of controls (n = 8), respectively; P < 0.05]. A similar reduction was observed for AQP3. The reduction in AQP expression in the proximal tubule and inner medullary collecting duct was confirmed by immunocytochemistry. Next, we found that intravenous alpha-MSH treatment of rats with ARF significantly reduced the ischemia-induced downregulation of renal AQPs and reduced the polyuria. In conclusion, the I/R injury is associated with markedly reduced expression of the collecting duct and proximal tubule AQPs, in association with an impairment of urinary concentration. Moreover, alpha-MSH treatment significantly prevented the reduction in expression of AQPs and renal functional defects. Thus decreased AQP expression is likely to contribute to the impairment in urinary concentration in the postischemic period.
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PMID:Reduced abundance of aquaporins in rats with bilateral ischemia-induced acute renal failure: prevention by alpha-MSH. 1048 25

The high water permeability characteristic of mammalian red cell membranes is now known to be caused by the protein AQP1. This channel freely permits movement of water across the cell membrane, but it is not permeated by other small, uncharged molecules or charged solutes. AQP1 is a tetramer with each subunit containing an aqueous pore likened to an hourglass formed by obversely arranged tandem repeats. Cryoelectron microscopy of reconstituted AQP1 membrane crystals has revealed the three-dimensional structure at 3-6 A. AQP1 is distributed in apical and basolateral membranes of renal proximal tubules and descending thin limbs as well as capillary endothelia. Ten mammalian aquaporins have been identified in water-permeable tissues and fall into two groupings. Orthodox aquaporins are water-selective and include AQP2, a vasopressin-regulated water channel in renal collecting duct, in addition to AQP0, AQP4, and AQP5. Multifunctional aquaglyceroporins AQP3, AQP7, and AQP9 are permeated by water, glycerol, and some other solutes. Aquaporins are being defined in numerous other species including amphibia, insects, plants, and microbials. Members of the aquaporin family are implicated in numerous physiological processes as well as the pathophysiology of a wide range of clinical disorders.
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PMID:Cellular and molecular biology of the aquaporin water channels. 1087 56

The mechanisms underlying age-related polyuria were investigated in 10- and 30-mo-old female WAG/Rij rats. Urinary volume and osmolality were 3.9 +/- 0.3 ml/24 h and 2,511 +/- 54 mosmol/kgH(2)O in adult rats and 12.8 +/- 0.8 ml/24 h and 1,042 +/- 44 mosmol/kgH(2)O in senescent animals. Vasopressin V(2) receptor mRNA did not significantly differ between 10 and 30 mo, and [(3)H]vasopressin binding sites in membrane papilla were reduced by 30%. The cAMP content of the papilla was unchanged with age, whereas papillary osmolality was significantly lowered in senescent animals. The expression of aquaporin-1 (AQP1) and -4 was mostly unaltered from 10 to 30 mo. In contrast, aquaporin-2 (AQP2) and -3 (AQP3) expression was downregulated by 80 and 50%, respectively, and AQP2 was markedly redistributed into the intracellular compartment, in inner medulla of senescent animals, but not in renal cortex. These results indicate that age-related polyuria is associated with a downregulation of AQP2 and AQP3 expression in the medullary collecting duct, which is independent of vasopressin-mediated cAMP accumulation.
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PMID:Downregulation of aquaporin-2 and -3 in aging kidney is independent of V(2) vasopressin receptor. 1089 96

The phenotype analysis of transgenic mice deficient in specific aquaporin water channels has provided new insights into the role of aquaporins in organ physiology. AQP1-deficient mice are polyuric and are unable to concentrate their urine in response to water deprivation or vasopressin administration. AQP1 deletion reduces osmotic water permeability in the proximal tubule, thin descending limb of Henle and vasa recta, resulting in defective proximal tubule fluid absorption and medullary countercurrent exchange. Mice lacking AQP3, a basolateral membrane water channel expressed mainly in the cortical collecting duct, are remarkably polyuric but are able to generate a partly concentrated urine after water deprivation. In contrast, mice lacking AQP4, a water channel expressed mainly in the inner medullary collecting duct, manifest only a mild defect in maximum urinary concentrating ability. These data, together with phenotype analyses of the brain, lung, salivary gland, and gastrointestinal organs, support the paradigm that aquaporins can facilitate near-isosmolar transepithelial fluid absorption/secretion as well as rapid vectorial water movement driven by osmotic gradients. The phenotype data obtained from aquaporin knockout mice suggest the utility of aquaporin blockers as novel diuretic agents.
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PMID:Physiological importance of aquaporins: lessons from knockout mice. 1099 Mar 71

Hereditary non-X-linked nephrogenic diabetes insipidus (NDI) is caused by mutations in the aquaporin-2 (AQP2) water channel. In transfected cells, the human disease-causing mutant AQP2-T126M is retained at the endoplasmic reticulum (ER) where it is functional and targetable to the plasma membrane with chemical chaperones. A mouse knock-in model of NDI was generated by targeted gene replacement using a Cre-loxP strategy. Along with T126M, mutations H122S, N124S, and A125T were introduced to preserve the consensus sequence for N-linked glycosylation found in human AQP2. Breeding of heterozygous mice yielded the expected Mendelian distribution with 26 homozygous mutant offspring of 99 live births. The mutant mice appeared normal at 2-3 days after birth but failed to thrive and generally died by day 6 if not given supplemental fluid. Urine/serum analysis showed a urinary concentrating defect with serum hyperosmolality and low urine osmolality that was not increased by a V2 vasopressin agonist. Northern blot analysis showed up-regulated AQP2-T126M transcripts of identical size to wild-type AQP2. Immunoblots showed complex glycosylation of wild-type AQP2 but mainly endoglycosidase H-sensitive core glycosylation of AQP2-T126M indicating ER-retention. Biochemical analysis revealed that the AQP2-T126M protein was resistant to detergent solubilization. Kidneys from mutant mice showed collecting duct dilatation, papillary atrophy, and unexpectedly, some plasma membrane AQP2 staining. The severe phenotype of the AQP2 mutant mice compared with that of mice lacking kidney water channels AQP1, AQP3, and AQP4 indicates a critical role for AQP2 in neonatal renal function in mice. Our results establish a mouse model of human autosomal NDI and provide the first in vivo biochemical data on a disease-causing AQP2 mutant.
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PMID:Neonatal mortality in an aquaporin-2 knock-in mouse model of recessive nephrogenic diabetes insipidus. 1103 38


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