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10.1073/pnas.0306924101 http://scihub22266oqcxt.onion/10.1073/pnas.0306924101 15070779!384808!15070779     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Proc+Natl+Acad+Sci+U+S+A 2004 ; 101 (13): 4690-4 Nephropedia Template TP {{tp|p=15070779|t=2004. Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins |pdf=|usr=}}{{15070779}} gab.com Text Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins JO: Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=15070779 #FOAvip Mutations in the WNK4 gene cause pseudohypoaldosteronism type II (PHAII), an autosomal-dominant disorder of hyperkalemia and hypertension. The target molecules of this putative kinase and the molecular mechanisms by which the mutations cause the phenotypes are currently unknown. Although recent reports found that expression of WNK4 in Xenopus oocytes causes inhibition of the thiazide-sensitive NaCl cotransporter and the renal K channel ROMK, there may be additional targets of WNK4. For example, an increase in paracellular chloride permeability has been postulated to be a mediator of PHAII pathogenesis, a possibility supported by the localization of WNK4 at tight junctions in vivo. To determine the validity of this hypothesis, we measured transepithelial Na and Cl permeability in Madin-Darby canine kidney II cells stably expressing wild-type or a pathogenic mutant of WNK4. We found that transepithelial paracellular Cl permeability was increased in cells expressing a disease-causing mutant WNK4 (D564A) but that Na permeability was decreased slightly. Furthermore, WNK4 bound and phosphorylated claudins 1-4, major tight-junction membrane proteins known to be involved in the regulation of paracellular ion permeability. The increases in phosphorylation of claudins were greater in cells expressing the mutant WNK4 than in cells expressing wild-type protein. These results clearly indicate that the pathogenic WNK4 mutant possesses a gain-of-function activity and that the claudins may be important molecular targets of WNK4 kinase. The increased paracellular "chloride shunt" caused by the mutant WNK4 could be the pathogenic mechanism of PHAII. Twit Text FOAVip Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins ????Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=15070779 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=15070779 #FOAvip English Wikipedia <ref>{{Cite pmid|15070779}}</ref> Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins #MMPMID15070779 Yamauchi K; Rai T; Kobayashi K; Sohara E; Suzuki T; Itoh T; Suda S; Hayama A; Sasaki S; Uchida S Proc Natl Acad Sci U S A 2004[Mar]; 101 (13): 4690-4 PMID15070779show ga Mutations in the WNK4 gene cause pseudohypoaldosteronism type II (PHAII), an autosomal-dominant disorder of hyperkalemia and hypertension. The target molecules of this putative kinase and the molecular mechanisms by which the mutations cause the phenotypes are currently unknown. Although recent reports found that expression of WNK4 in Xenopus oocytes causes inhibition of the thiazide-sensitive NaCl cotransporter and the renal K channel ROMK, there may be additional targets of WNK4. For example, an increase in paracellular chloride permeability has been postulated to be a mediator of PHAII pathogenesis, a possibility supported by the localization of WNK4 at tight junctions in vivo. To determine the validity of this hypothesis, we measured transepithelial Na and Cl permeability in Madin-Darby canine kidney II cells stably expressing wild-type or a pathogenic mutant of WNK4. We found that transepithelial paracellular Cl permeability was increased in cells expressing a disease-causing mutant WNK4 (D564A) but that Na permeability was decreased slightly. Furthermore, WNK4 bound and phosphorylated claudins 1-4, major tight-junction membrane proteins known to be involved in the regulation of paracellular ion permeability. The increases in phosphorylation of claudins were greater in cells expressing the mutant WNK4 than in cells expressing wild-type protein. These results clearly indicate that the pathogenic WNK4 mutant possesses a gain-of-function activity and that the claudins may be important molecular targets of WNK4 kinase. The increased paracellular "chloride shunt" caused by the mutant WNK4 could be the pathogenic mechanism of PHAII. |Animals[MESH] |Cell Line[MESH] |Cell Membrane Permeability/*physiology[MESH] |Chlorides/*metabolism[MESH] |Cloning, Molecular[MESH] |Dogs[MESH] |Humans[MESH] |Kidney[MESH] |Membrane Proteins/*metabolism[MESH] |Mutagenesis, Site-Directed[MESH] |Phosphorylation[MESH] |Protein Serine-Threonine Kinases/*genetics[MESH] |RNA, Messenger/genetics[MESH] |Reverse Transcriptase Polymerase Chain Reaction[MESH] |Sodium/physiology[MESH]Disease-causing mutant WNK4 increases paracellular chloride permeabili(epmc).pdf DeepDyve Pubget Overpricing