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10.1172/JCI61110 http://scihub22266oqcxt.onion/10.1172/JCI61110 23348737!3561795!23348737     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       J+Clin+Invest 2013 ; 123 (2): 657-65 Nephropedia Template TP {{tp|p=23348737|t=2013. Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension |pdf=|usr=}}{{23348737}} gab.com Text Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension JO: J Clin Invest http://www.kidney.de/pget.php?&tw=1&pmid=23348737 #FOAvip The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human beta/gammaENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high-Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of betaENaC, gammaENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the alphaENaC subunit, was reduced and proteolytic cleavage of alphaENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of beta/gammaENaC, but not alphaENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK. Twit Text FOAVip Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension ????J Clin Invest http://www.kidney.de/pget.php?&tw=1&pmid=23348737 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=23348737 #FOAvip English Wikipedia <ref>{{Cite pmid|23348737}}</ref> Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension #MMPMID23348737 Ronzaud C; Loffing-Cueni D; Hausel P; Debonneville A; Malsure SR; Fowler-Jaeger N; Boase NA; Perrier R; Maillard M; Yang B; Stokes JB; Koesters R; Kumar S; Hummler E; Loffing J; Staub O J Clin Invest 2013[Feb]; 123 (2): 657-65 PMID23348737show ga The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human beta/gammaENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high-Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of betaENaC, gammaENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the alphaENaC subunit, was reduced and proteolytic cleavage of alphaENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of beta/gammaENaC, but not alphaENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK. |Animals[MESH] |Blood Pressure[MESH] |Disease Models, Animal[MESH] |Endosomal Sorting Complexes Required for Transport/*deficiency/genetics/metabolism[MESH] |Epithelial Sodium Channels/metabolism[MESH] |Humans[MESH] |Hypertension/*etiology/genetics/physiopathology[MESH] |Kidney Tubules/*physiopathology[MESH] |Liddle Syndrome/etiology/genetics/physiopathology[MESH] |Mice[MESH] |Mice, Knockout[MESH] |Nedd4 Ubiquitin Protein Ligases[MESH] |Potassium Channels, Inwardly Rectifying/metabolism[MESH] |Potassium/blood/urine[MESH] |Receptors, Drug/*metabolism[MESH] |Sodium, Dietary/administration & dosage/adverse effects[MESH] |Sodium/blood/urine[MESH] |Solute Carrier Family 12, Member 3[MESH] |Symporters/*metabolism[MESH]Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hy(epmc).pdf DeepDyve Pubget Overpricing