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)

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

Aquaporin-2 (AQP2), the vasopressin-regulated water channel of the renal collecting duct, is dysregulated in numerous disorders of water balance in people and animals, including those associated with polyuria (urinary tract obstruction, hypokalemia, inflammation, and lithium toxicity) and with dilutional hyponatremia (syndrome of inappropriate antidiuresis, congestive heart failure, cirrhosis). Normal regulation of AQP2 by vasopressin involves 2 independent regulatory mechanisms: (1) short-term regulation of AQP2 trafficking to and from the apical plasma membrane, and (2) long-term regulation of the total abundance of the AQP2 protein in the cells. Most disorders of water balance are the result of dysregulation of processes that regulate the total abundance of AQP2 in collecting duct cells. In general, the level of AQP2 in a collecting duct cell is determined by a balance between production via translation of AQP2 mRNA and removal via degradation or secretion into the urine in exosomes. AQP2 abundance increases in response to vasopressin chiefly due to increased translation subsequent to increases in AQP2 mRNA. Vasopressin-mediated regulation of AQP2 gene transcription is poorly understood, although several transcription factor-binding elements in the 5' flanking region of the AQP2 gene have been identified, and candidate transcription factors corresponding to these elements have been discovered in proteomics studies. Here, we review progress in this area and discuss elements of vasopressin signaling in the collecting duct that may impinge on regulation of AQP2 in health and in the context of examples of polyuric diseases.
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PMID:Aquaporin-2 regulation in health and disease. 2313 Sep 44

Arginine-vasopressin (AVP) facilitates water reabsorption in renal collecting duct principal cells through regulation of the water channel aquaporin-2 (AQP2). The hormone binds to vasopressin V2 receptors (V2R) on the surface of the cells and stimulates cAMP synthesis. The cAMP activates protein kinase A (PKA), which initiates signaling that causes an accumulation of AQP2 in the plasma membrane of the cells facilitating water reabsorption from primary urine and fine-tuning of body water homeostasis. AVP-mediated PKA activation also causes an increase in the AQP2 protein abundance through a mechanism that involves dephosphorylation of AQP2 at serine 261 and a decrease in its poly-ubiquitination. However, the signaling downstream of PKA that controls the localization and abundance of AQP2 is incompletely understood. We carried out an siRNA screen targeting 719 kinase-related genes, representing the majority of the kinases of the human genome and analyzed the effect of the knockdown on AQP2 by high-content imaging and biochemical approaches. The screening identified 13 hits whose knockdown inhibited the AQP2 accumulation in the plasma membrane. Amongst the candidates was the so far hardly characterized cyclin-dependent kinase 18 (CDK18). Our further analysis revealed a hitherto unrecognized signalosome comprising CDK18, an E3 ubiquitin ligase, STUB1 (CHIP), PKA and AQP2 that controls the localization and abundance of AQP2. CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. STUB1 functions as an A-kinase anchoring protein (AKAP) tethering PKA to the protein complex and bridging AQP2 and CDK18. The modulation of the protein complex may lead to novel concepts for the treatment of disorders which are caused or are associated with dysregulated AQP2 and for which a satisfactory treatment is not available, e.g., hyponatremia, liver cirrhosis, diabetes insipidus, ADPKD or heart failure.
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PMID:Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP. 3216 29