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10.1681/ASN.2017111155 http://scihub22266oqcxt.onion/10.1681/ASN.2017111155 29848507!6050918!29848507     free     free     free Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       J+Am+Soc+Nephrol 2018 ; 29 (7): 1838-1848 Nephropedia Template TP {{tp|p=29848507|t=2018. The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway |pdf=|usr=}}{{29848507}} gab.com Text The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway JO: J Am Soc Nephrol http://www.kidney.de/pget.php?&tw=1&pmid=29848507 #FOAvip Background Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle's loop controls Ca(2+) excretion and NaCl reabsorption in response to extracellular Ca(2+) However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss.Methods We used a combination of in vitro and in vivo models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well.Results Thiazide-sensitive (22)Na(+) uptake assays in Xenopus laevis oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd(3+) In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC.Conclusions Activation of CaSR can increase NCC activity via the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca(2+) in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca(2+) reabsorption, further promoting hypercalciuria. Twit Text FOAVip The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway ????J Am Soc Nephrol http://www.kidney.de/pget.php?&tw=1&pmid=29848507 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=29848507 #FOAvip English Wikipedia <ref>{{Cite pmid|29848507}}</ref> The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway #MMPMID29848507 Bazua-Valenti S; Rojas-Vega L; Castaneda-Bueno M; Barrera-Chimal J; Bautista R; Cervantes-Perez LG; Vazquez N; Plata C; Murillo-de-Ozores AR; Gonzalez-Mariscal L; Ellison DH; Riccardi D; Bobadilla NA; Gamba G J Am Soc Nephrol 2018[Jul]; 29 (7): 1838-1848 PMID29848507show ga Background Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle's loop controls Ca(2+) excretion and NaCl reabsorption in response to extracellular Ca(2+) However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss.Methods We used a combination of in vitro and in vivo models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well.Results Thiazide-sensitive (22)Na(+) uptake assays in Xenopus laevis oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd(3+) In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC.Conclusions Activation of CaSR can increase NCC activity via the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca(2+) in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca(2+) reabsorption, further promoting hypercalciuria. |Adaptor Proteins, Signal Transducing[MESH] |Animals[MESH] |Carrier Proteins/genetics/metabolism[MESH] |Enzyme Activation/genetics[MESH] |HEK293 Cells[MESH] |Humans[MESH] |Imidazoles/pharmacology[MESH] |Male[MESH] |Mice[MESH] |Microfilament Proteins[MESH] |Oocytes[MESH] |Phenethylamines/pharmacology[MESH] |Phosphorylation/drug effects[MESH] |Propylamines/pharmacology[MESH] |Protein Kinase C/metabolism[MESH] |Protein Kinase Inhibitors/pharmacology[MESH] |Protein Serine-Threonine Kinases/genetics/*metabolism[MESH] |Pyrrolidines/pharmacology[MESH] |Receptors, Calcium-Sensing/genetics/*metabolism[MESH] |Receptors, G-Protein-Coupled/*metabolism[MESH] |Signal Transduction[MESH] |Sodium/*metabolism[MESH] |Solute Carrier Family 12, Member 1/antagonists & inhibitors/metabolism[MESH] |Solute Carrier Family 12, Member 3/metabolism[MESH] |Transfection[MESH] |Xenopus Proteins/metabolism[MESH]The Calcium-Sensing Receptor Increases Activity of the Renal NCC throu(epmc).pdf DeepDyve Pubget Overpricing