Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent monogenic hereditary disease as well as the most studied inherited kidney disease. Two drugs have recently been authorized that can slow down the progression of the disease: Tolvaptan (vasopressin receptor antagonist) and Octreotide-LAR (long-acting somatostatin analogue); they both are able to reduce the activity of cyclic adenosine monophosphate (cAMP) and therefore have anti-proliferative and anti-secretory effects. This review analyzes the main trials published to date demonstrating the effects on disease progression in patients with ADPKD and illustrates the indications for identifying subjects eligible for therapy.
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PMID:[ADPKD treatment: Tolvaptan and Octreotide]. 3183 Mar 92

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

Autosomal dominant polycystic kidney disease (ADPKD) is incurable and occurs once in every 1,000 births. Confirmation of AKPKD is made through imaging and a positive family history. Symptoms typically appear in mid-life and include kidney, side, and/or back pain related to the rupture of kidney cysts, renal stones, infection, pressure of cysts against other organs, and stretching of the renal capsule. In addition to end stage renal disease, cerebral aneurysm may also be a threat to individuals with this diagnosis. Recent clinical trials have shown that tolvaptan, a vasopressin-2 receptor antagonist, produced a moderate to significant reduction in total kidney volume and improved function, leading to its recent approval by the U.S. Federal Drug Administration for treatment of patients with ADPKD. This article provides a comprehensive look at the pathophysiology of ADPKD, pharmacokinetics and pharmacodynamics of tolvaptan, and tolvaptan's clinical implications, effects, and contraindications. In addition, we present a case study discussing tolvaptan's clinical usefulness and address patient concerns in an adult presenting with rapidly progressing ADPKD.
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PMID:Tolvaptan for Autosomal Dominant Polycystic Kidney Disease: Pharmacokinetics and Implications for Practice. 3234 88


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