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)

Located in the principal cells of the collecting duct, aquaporin-2 (AQP2) is responsible for the regulated water reabsorption in the kidney and is indispensable for the maintenance of body water balance. Disregulation or malfunctioning of AQP2 can lead to severe diseases such as nephrogenic diabetes insipidus, congestive heart failure, liver cirrhosis and pre-eclampsia. Here we present the crystallization of recombinantly expressed human AQP2 into two-dimensional protein-lipid arrays and their structural characterization by atomic force microscopy and electron crystallography. These crystals are double-layered sheets that have a diameter of up to 30 microm, diffract to 3 A(-1) and are stacked by contacts between their cytosolic surfaces. The structure determined to 4.5 A resolution in the plane of the membrane reveals the typical aquaporin fold but also a particular structure between the stacked layers that is likely to be related to the cytosolic N and C termini.
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PMID:The 4.5 A structure of human AQP2. 1592 55

Vasopressin, or anti-diuretic hormone, is a peptide hormone that plays an important role in the regulation of extracellular volume and its osmolarity. Increased plasma osmolarity and hypovolemia are the principal physiological stimuli for vasopressin release. The biological effects of vasopressin on its target organs are mediated by two receptors: V1 and V2. V2 is localized to renal tissue and its activation leads to upregulation of aquaporin-2 in the collecting duct allowing the reabsorption of large volumes of water. In contrast, V1 is expressed mainly in blood vessel walls, and its activation results in vascoconstriction. Besides the physiological importance of the vasopressin system, it also plays a crucial role in the pathogenesis of various diseases, including congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion. These clinical syndromes are characterized by enhanced plasma levels of vasopressin, which correlate with the severity of the disease and largely contribute to the development of edema and hyponatremia. Great efforts have been invested in attempting to develop selective and long lasting vasopressin antagonists. However, general medicine and particularly nephrology, suffered from the absence of non-peptide vasopressin blockers that could be taken orally. The last few years have witnessed the development of numerous selective vasopressin antagonists with high bioavailability and long half-lives. Administration of these antagonists to patients with congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion substantially enhanced free water excretion and moderately increased serum sodium concentrations. No side effects, except for mild increased thirst sensation, were observed. The present review focuses on the recent developments in vasopressin research, with special emphasize on the development of selective non-peptide antagonists and their clinical use.
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PMID:[Vasopressin V2 receptor antagonists: pharmacological properties and clinical implications]. 1640 Jul 90

Several experimental models of cirrhosis have shown dysregulation of renal aquaporins in different phases of liver disease. We investigated the urinary excretion of both aquaporin-1 and aquaporin-2 in patients with cirrhosis at different stages of the disease. Twenty-four-hour urine was collected from 11 healthy volunteers, 13 patients with compensated cirrhosis (without ascites), and 20 patients with decompensated cirrhosis (11 with ascites without renal failure and 9 with hepatorenal syndrome). Aquaporin-1 and aquaporin-2 excretion was analyzed by immunoblotting. Urinary aquaporin-2 excretion was reduced in patients with cirrhosis compared to healthy subjects. A progressive decrease in urinary aquaporin-2 excretion was observed as the severity of cirrhosis increased, from compensated cirrhosis to cirrhosis with ascites and hepatorenal syndrome. Patients with hyponatremia had lower urinary aquaporin-2 excretion than patients without hyponatremia. Vasopressin plasma level did not correlate with aquaporin-2 excretion. There were no differences between healthy subjects and patients with cirrhosis with or without ascites in urinary excretion of aquaporin-1, but urinary aquaporin-1 excretion of those with hepatorenal syndrome was extremely low. In conclusion, patients with cirrhosis appear to exhibit a decreased abundance of renal aquaporin-2 and therefore lower water permeability in the collecting tubules. This may represent an adaptive renal response to sodium retention, with expansion of extracellular fluid volume and dilutional hyponatremia observed in those who have cirrhosis with ascites. Finally, aquaporin-1 does not appear to play a role in the progressive dysregulation of extracellular fluid volume in cirrhosis.
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PMID:Aquaporin-1 and aquaporin-2 urinary excretion in cirrhosis: Relationship with ascites and hepatorenal syndrome. 1713 93

Unlike the more commonly used diuretics, aquaretic agents can induce an increase in urinary volume without incurring a loss of electrolytes. These molecules belong to a family of vasopressin receptor antagonists, V2 in particular, that regulate optional renal water re-absorption via the synthesis and expression of aquaporin-2. In view of their properties, they have become the agent of choice in the treatment of hyponatremic states with water retention, and different studies have demonstrated that they are more effective and practical to use than other traditional approaches in the treatment of diseases such as cirrhosis-related ascites, SIADH and, above all, heart failure. However, the future probably holds the promise of new and unexpected applications for this type of drug in the treatment of several conditions, including polycystic kidney and glomerular disease, glaucoma and Meniere's syndrome.
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PMID:Aquaretic agents: what's beyond the treatment of hyponatremia? 1743 Jan 86

Vasopressin is a critical regulator of water homeostasis. There are two major receptors for vasopressin: V1 and V2 receptors. Disturbances in water balance are commonly encountered in clinical practice and can be divided into disorders of urinary dilution and concentration. The major representatives of such disorders are diabetes insipidus and the syndrome of inappropriate secretion of antidiuretic hormone (SI ADH). Recent studies show that genetic forms of nephrogenic diabetes insipidus are due to mutations in the genes coding for the vasopressin V2 receptor (V2R) or aquaporin-2 (AQP2). Identification of the genes involved and analysis of the cellular fate of the V2R and AQP2 mutants are relevant for understanding the functioning of the V2R and AQP2 protein. These developments also have implications for future therapeutic options. The development of nonpeptide vasopressin receptor antagonists (VRAs) offers prospects for the treatment of euvolaemic (SI ADH) or hypervolaemic hyponatraemia (congestive heart failure or cirrhosis). Several nonpeptide VRAs are now in various stages of clinical trials. At present, only conivaptan is registered by the FD A for intravenous treatment of euvolaemic and hypervolaemic hyponatremia. A recent long-term study comparing tolvaptan with placebo in patients with chronic heart failure showed no reduction in risk of death and hospitalisation.
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PMID:Water in health and disease: new aspects of disturbances in water metabolism. 1795 51

The discovery of four major water channels in the kidney, namely aquaporins (AQP) 1, 2, 3 and 4, has allowed a substantial increase in our understanding of renal water regulation in health and disease. This review discusses the renal aquaporin water channels in the urinary dilution and concentrating defects in cardiac failure, cirrhosis, syndrome of inappropriate hormone secretion, pregnancy, hypothyroidism, isolated glucocorticoid deficiency, isolated mineralocorticoid deficiency, primary polydipsia, acquired and genetic nephrogenic diabetes insipidus.
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PMID:Aquaporin-related disorders of water homeostasis. 1799 67

The biological importance of the aquaporin family of water channels was recently acknowledged by the 2003 Nobel Prize for Chemistry awarded to the discovering scientist Peter Agre. Among the pleiotropic roles exerted by aquaporins in nature in both health and disease, the review addresses the latest acquisitions about the expression and regulation, as well as physiology and pathophysiology of aquaporins in the hepatobiliary tract. Of note, at least seven out of the thirteen mammalian aquaporins are expressed in the liver, bile ducts and gallbladder. Aquaporins are essential for bile water secretion and reabsorption, as well as for plasma glycerol uptake by the hepatocyte and its conversion to glucose during starvation. Novel data are emerging regarding the physio-pathological involvement of aquaporins in multiple diseases such as cholestases, liver cirrhosis, obesity and insulin resistance, fatty liver, gallstone formation and even microparasite invasion of intrahepatic bile ducts. This body of knowledge represents the mainstay of present and future research in a rapidly expanding field.
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PMID:Aquaporins in the hepatobiliary tract. Which, where and what they do in health and disease. 1817 45

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

Water is the most abundant molecule in any cell. Specialized membrane channel, proteins called aquaporins, facilitate water transport across cell membranes. At least seven aquaporins (AQP): 1, 2, 3, 4, 6, 7, and 11 are expressed in the kidneys. Aquaporins play a role in both the short-term and long-term regulation of water balance as well as in the pathophysiology of water balance disorders. Aquaporin is composed of a single peptide chain consisting of approximately 270 amino acids. Inherited central and nephrogenic diabetes insipidus are primarily due to the decreased expression of AQP2 while mutation in the AQP2 molecule is responsible for inherited central diabetes insipidus. In acquired causes of nephrogenic diabetes insipidus, there is a downregulation of AQP2 expression in the inner medulla of the kidney. Nephrotic syndrome is characterized by excessive sodium and water reabsorption, although in spite of this, patients do not develop hyponatremia. There is a marked downregulation of both AQP2 and AQP3 expression, which could be a physiologic response to extracellular water reabsorption in patients with nephrotic syndrome. There are some conditions in which aquaporin expression has been found to increase such as experimentally induced heart failure, cirrhosis, and pregnancy. Some drugs such as cisplatin and cyclosporine, also alter the expression of aquaporins. The three-pore model of peritoneal transport depicts the importance of aquaporins. Thus, the understanding of renal water channels has solved the mystery behind many water balance disorders. Further insights into the molecular structure and biology of aquaporins will help to lay a foundation for the development of future drugs.
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PMID:Aquaporins: The renal water channels. 2014 13


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