Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In patients with liver cirrhosis, impaired water and sodium excretion has been incriminated in the pathogenesis of ascites formation. Increased reabsorption of water in the distal nephron has been shown to play an important role in water retention in cirrhotic rat kidneys. Recently, a complementary DNA (cDNA) for the vasopressin-regulated water channel (the aquaporin of the apical membrane of the kidney collecting duct [AQP-CD]) has been cloned. It is suggested that AQP-CD plays an important role in renal water handling. Therefore, in the present study, to investigate the pathogenic role of the water channel in water retention in liver cirrhosis, gene expression of AQP-CD in the kidney was evaluated in cirrhotic rats. Liver cirrhosis was induced by an intraperitoneal administration of carbon tetrachloride twice a week for 12 weeks in 14 rats. Messenger RNA expression of AQP-CD in whole kidney homogenates determined by Northern blot hybridization was significantly increased in cirrhotic rats (147%; P < .01) and dehydrated rats (206%; P < .0001) compared with control rats. Protein expression of AQP-CD in the homogenates of kidney medulla determined by Western blot analysis was significantly increased in cirrhotic rats (203%; P < .03) compared with control rats. Furthermore, mRNA expression of AQP-CD in the kidney showed a significant correlation with the volume of ascites in cirrhotic rats (r = .62, P < .02). No significant difference was observed in water intake, urinary volume, serum osmolality, serum sodium, and creatinine clearance between control and cirrhotic rats, suggesting that dehydration was unlikely in cirrhotic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased gene expression of water channel in cirrhotic rat kidneys. 752 8

We determined whether aquaporin of collecting duct (AQP-CD) is involved in pathogenesis of water retention in rats with experimental models of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and liver cirrhosis. SIADH rats were made by administering 1-desamino-8-D-arginine vasopressin (DDAVP) subcutaneously and providing them with a liquid diet. Serum Na levels decreased to < 120 meq/l on day 2, and hyponatremia persisted throughout the rest of observation period. Six hours after the DDAVP infusion, the expression of AQP-CD mRNA significantly increased by 198%, followed by > 144% increases in its expression during the 14-day observation period. On day 7, the increased expression of AQP-CD mRNA was abolished after the administration of an antidiuretic, nonpeptide arginine vasopressin (AVP) antagonist, OPC-31260, which was closely related to a marked diuresis and a prompt normalization of serum Na levels in SIADH rats. Rats were made cirrhotic by injecting a mixture of carbon tetrachloride and olive oil subcutaneously for 3 mo. The expression of AQP-CD mRNA was increased by 164% in the decompensated cirrhotic rats. The blockade of AVP action by OPC-31260 significantly diminished its expression. These results indicate that water channel AQP-CD plays an important role in water retention in pathological states of SIADH and liver cirrhosis.
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PMID:Role of water channel AQP-CD in water retention in SIADH and cirrhotic rats. 859 89

The homotetrameric aquaporin-2 (AQP2) water channel is essential for the concentration of urine and of critical importance in diseases with water dysregulation, such as nephrogenic diabetes insipidus, congestive heart failure, liver cirrhosis and pre-eclampsia. The structure of human AQP2 is a prerequisite for understanding its function and for designing specific blockers. To obtain sufficient amounts of AQP2 for structural analyses, we have expressed recombinant his-tagged human AQP2 (HT-AQP2) in the baculovirus/insect cell system. Using the protocols outlined in this study, 0.5 mg of pure HT-AQP2 could be obtained per liter of bioreactor culture. HT-AQP2 had retained its homotetrameric structure and exhibited a single channel water permeability of 0.93+/-0.03x10(-13) cm3/s, similar to that of other AQPs. Thus, the baculovirus/insect cell system allows large-scale expression of functional recombinant human AQP2 that is suitable for structural studies.
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PMID:Large-scale purification of functional recombinant human aquaporin-2. 1153 54

Alterations in water metabolism are present in conditions such as diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, cardiac failure, cirrhosis, and pregnancy. Recent advances in molecular biology have enhanced our understanding of disordered water metabolism in these conditions. This review examines the roles of central vasopressin synthesis and release and collecting duct vasopressin V2 receptor and aquaporin-2 water channel regulation in water-losing and water-retaining states.
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PMID:Water-losing and water-retaining states: role of water channels and vasopressin receptor antagonists. 1197 94

Vasopressin (AVP) stimulates collecting duct water reabsorption through cAMP-mediated membrane targeting and increased expression of the aquaporin-2 (AQP2) water channel. Rats with liver cirrhosis induced by common bile duct ligation (CBL) show decreased protein expression of AQP2 despite increased plasma concentrations of AVP. The present study was conducted to investigate possible mechanisms behind this uncoupling of AVP signaling. The rats were examined 4 wk after CBL or sham operation. The CBL rats had increased plasma AVP concentrations (CBL: 3.2 +/- 0.2 vs. sham: 1.4 +/- 0.4 pg/ml, P < 0.05) and reduced AQP2 (0.62 +/- 0.11) and phosphorylated AQP2 (0.50 +/- 0.06) protein expression compared with sham-operated rats. However, examination of subcellular AQP2 localization by immunohistochemistry showed unchanged plasma membrane targeting in CBL rats, indicating a sustained ability of AQP2 short-term regulation. In a separate series of animals, thirsting was found to normalize AQP2 expression, indicating that AVP uncoupling in CBL rats is a physiological compensatory mechanism aimed at avoiding dilutional hyponatremia. Studies on microdissected collecting ducts from CBL rats showed decreased cAMP accumulation in response to AVP stimulation. The presence of the nonspecific phosphodiesterase inhibitor IBMX normalized the cAMP accumulation, indicating that cAMP-phosphodiesterase activity is increased in CBL rats. However, in contrast to this, Western blotting showed a decreased expression of several phosphodiesterase splice variants. We conclude that CBL rats develop an escape from AVP to prevent the formation of dilutional hyponatremia in response to increased plasma AVP concentrations. The mechanism behind AVP escape seems to involve decreased collecting duct sensitivity to AVP as a result of increased cAMP-phosphodiesterase activity.
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PMID:Uncoupling of vasopressin signaling in collecting ducts from rats with CBL-induced liver cirrhosis. 1517 84

Impaired urinary dilution leading to water retention and hyponatremia may occur in patients with cardiac failure, cirrhosis, pregnancy, oxytocin administration, hypothyroidism, glucocorticoid, and mineralocorticoid deficiency. The mechanisms for these defects predominantly involve the nonosmotic stimulation of arginine vasopressin release with up-regulation of aquaporin 2 water channel expression and trafficking to the apical membrane of the principal cells of the collecting duct. These perturbations are reversed by V2 vasopressin receptor antagonists. In contrast, urinary concentration defects leading to polyuria are vasopressin resistant. They may involve several factors, such as impaired countercurrent concentration secondary to down-regulation of Na-K-2Cl cotransporter. Vasopressin-resistant down-regulation of aquaporin 2 expression has also been described as a factor in impaired urinary concentration.
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PMID:Vasopressin and aquaporin 2 in clinical disorders of water homeostasis. 1851 89

Impaired urinary dilution leading to water retention and hyponatremia may occur in patients with cardiac failure, cirrhosis, pregnancy, hypothyroidism, glucocorticoid and mineralocorticoid deficiency. The mechanisms for these defects predominantly involve the non-osmotic stimulation of arginine vasopressin release with upregulation of aquaporin 2 water channel expression and trafficking to the apical membrane of the principal cells of the collecting duct. These perturbations are reversed by V2 vasopressin receptor antagonists. In contrast, urinary concentration defects leading to polyuria are vasopressin-resistant. They may involve several factors, such as impaired counter-current concentration secondary to downregulation of Na-K-2Cl co-transporter. Vasopressin-resistant downregulation of aquaporin 2 expression has also been described as a factor in impaired urinary concentration.
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PMID:Molecular mechanisms of clinical concentrating and diluting disorders. 1865 7

The aquaporin (AQP) water channel plays an important role in the regulation of water. AQP2 is expressed in the collection duct of the kidney, serving as the final channel that helps to regulate water excretion in the kidneys and affecting the regulation of water and hyponatremia in cirrhotic patients. So far, research on aquaporin expression in cirrhosis has had various results. The purpose of this study is to investigate the factors that affect the regulation of expression of AQP in patients with cirrhosis. The study comprised 81 cirrhosis patients and 18 control subjects. In each group, 24-h urine was collected and nitric oxide and vasopressin levels were measured in the blood. The amount of urinary AQP was measured by Western blot. In this study, the positivity rate and amount of expression of AQP was higher in the cirrhotic group than that of the control group. AQP expression in urine was also compared between the groups with use of diuretics and the groups with no use of diuretics. A 57.4% positivity was observed with the former, whereas a 51.5% was seen in the latter. No significance was found between the groups (P = 0.581). Expression of AQP in compensated cirrhotic patients is significantly higher than decompensated cirrhotic patients and is especially higher in cirrhotic patients with ascites than with no ascites. There is no relationship between the concentration of vasopressin and expression of AQP. Concentration of serum NOx is higher in cirrhotic patients than the control group and there is a positive association between the concentration of serum nitric oxide and AQP in urine. In conclusion, expression of AQP is increased in cirrhotic patients and is significantly higher in patients with ascites. There is a positive association between the expression of AQP and concentration of serum nitric oxide.
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PMID:Aquaporin-2 urinary excretion in cirrhosis: relationship to vasopressin and nitric oxide. 1949 75

The aquaporin (AQP) water channel is expected to play a decisive role of hyponatremia and water retention in cirrhotic patients. Despite the importance of the water channel, however, previous findings vary widely when it concerns AQP2 of the kidneys in subjects with cirrhosis. The purpose of this study was to investigate the expression of AQP2 in the distal renal tubule in cirrhosis, and the presence of the nitric oxide-AQP2 signaling pathway as a possible vasopressin-aquaporin-independent pathway. Sixty male Wister rats were assigned to six groups: (1) control; (2) TAA (thioacetamide); (3) TAA with nitric oxide donor; (4) TAA with nitric oxide inhibitor; (5) TAA with HMG CoA reductase inhibitor; (6) TAA with tetrahydrobiopterin. Immunohistochemical staining for AQP2, real-time polymerase chain reaction (PCR) for AQP2 and 3, citrulline assay, and renal cGMP concentration were measured. The AQP2-positivity of cirrhotic rats were higher than the controls (P < 0.05). The AQP2-positivity decreased in the nitric oxide donor group, but the proportion rose back up when the subjects were injected with the nitric oxide inhibitor (P < 0.05). The expression of AQP2 and AQP3 mRNA was also found to show an increase in the cirrhotic group as compared with the normal controls (P < 0.05). The cirrhotic group administered with nitric oxide donor showed a significant decline in the expression of the mRNA. The control group's cGMP concentration was lower than that of the cirrhotic group (P < 0.05), but a comparison of the two groups injected with nitric oxide modulators, such as statin and BH4, did not show significant differences in the cGMP concentration level. The expression of AQP2 of the kidneys increased in the cirrhotic rats. AQP2 had relations to the activity changes of nitric oxide synthetase.
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PMID:The role of nitric oxide in the expression of renal aquaporin 2 in a cirrhotic rat model: does an AVP-independent mechanism exist for the regulation of AQP2 expression? 1951 35

Changes in hepatic vasculature accompany fibrogenesis, and targeting angiogenic molecules often attenuates fibrosis in animals. Aquaporin-1 (AQP1) is a water channel, overexpressed in cirrhosis, that promotes angiogenesis by enhancing endothelial invasion. The effect of AQP1 on fibrogenesis in vivo and the mechanisms driving AQP1 expression during cirrhosis remain unclear. The purpose of this study was to test the effect of AQP1 deletion in cirrhosis and explore mechanisms regulating AQP1. After bile duct ligation, wild-type mice overexpress AQP1 that colocalizes with vascular markers and sites of robust angiogenesis. AQP1 knockout mice demonstrated reduced angiogenesis compared with wild-type mice, as evidenced by immunostaining and endothelial invasion/proliferation in vitro. Fibrosis and portal hypertension were attenuated based on immunostaining, portal pressure, and spleen/body weight ratio. AQP1 protein, but not mRNA, was induced by hyperosmolality in vitro, suggesting post-transcriptional regulation. Endothelial cells from normal or cirrhotic mice were screened for microRNA (miR) expression using an array and a quantitative PCR. miR-666 and miR-708 targeted AQP1 mRNA and were decreased in cirrhosis and in cells exposed to hyperosmolality, suggesting that these miRs mediate osmolar changes via AQP1. Binding of the miRs to the untranslated region of AQP1 was assessed using luciferase assays. In conclusion, AQP1 promotes angiogenesis, fibrosis, and portal hypertension after bile duct ligation and is regulated by osmotically sensitive miRs.
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PMID:Aquaporin-1 promotes angiogenesis, fibrosis, and portal hypertension through mechanisms dependent on osmotically sensitive microRNAs. 2185 40


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