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10.1172/jci.insight.96700 http://scihub22266oqcxt.onion/10.1172/jci.insight.96700 29263298!5752287!29263298     free     free     free Deprecated: Implicit conversion from float 225.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 225.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 225.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 225.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       JCI+Insight 2017 ; 2 (24): ä Nephropedia Template TP {{tp|p=29263298|t=2017. Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects |pdf=|usr=}}{{29263298}} gab.com Text Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects JO: JCI Insight http://www.kidney.de/pget.php?&tw=1&pmid=29263298 #FOAvip Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) cause the disease familial hyperkalemic hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-Delta9) increases abundance of With-No-Lysine [K] Kinase 4 (WNK4), with excessive activation of the downstream Sterile 20 (STE20)/SPS-1-related proline/alanine-rich kinase (SPAK) increasing phosphorylation of the Na+-Cl- cotransporter (NCC). CUL3-Delta9 promotes its own degradation via autoubiquitination, leading to the hypothesis that Cul3 haploinsufficiency causes FHHt. To directly test this, we generated Cul3 heterozygous mice (CUL3-Het), and Cul3 heterozygotes also expressing CUL3-Delta9 (CUL3-Het/Delta9), using an inducible renal epithelial-specific system. Endogenous CUL3 was reduced to 50% in both models, and consistent with autoubiquitination, CUL3-Delta9 protein was undetectable in CUL3-Het/Delta9 kidneys unless primary renal epithelia cells were cultured. Abundances of WNK4 and phosphorylated NCC did not differ between control and CUL3-Het mice, but they were elevated in CUL3-Het/Delta9 mice, which also displayed higher plasma [K+] and blood pressure. Abundance of phosphorylated Na+-K+-2Cl- cotransporter (NKCC2) was also increased, which may contribute to the severity of CUL3-Delta9-mediated FHHt. WNK4 and SPAK localized to puncta in NCC-positive segments but not in NKCC2-positive segments, suggesting differential effects of CUL3-Delta9. These results indicate that Cul3 haploinsufficiency does not cause FHHt, but dominant effects of CUL3-Delta9 are required. Twit Text FOAVip Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects ????JCI Insight http://www.kidney.de/pget.php?&tw=1&pmid=29263298 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=29263298 #FOAvip English Wikipedia <ref>{{Cite pmid|29263298}}</ref> Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects #MMPMID29263298 Ferdaus MZ; Miller LN; Agbor LN; Saritas T; Singer JD; Sigmund CD; McCormick JA JCI Insight 2017[Dec]; 2 (24): ä PMID29263298show ga Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) cause the disease familial hyperkalemic hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-Delta9) increases abundance of With-No-Lysine [K] Kinase 4 (WNK4), with excessive activation of the downstream Sterile 20 (STE20)/SPS-1-related proline/alanine-rich kinase (SPAK) increasing phosphorylation of the Na+-Cl- cotransporter (NCC). CUL3-Delta9 promotes its own degradation via autoubiquitination, leading to the hypothesis that Cul3 haploinsufficiency causes FHHt. To directly test this, we generated Cul3 heterozygous mice (CUL3-Het), and Cul3 heterozygotes also expressing CUL3-Delta9 (CUL3-Het/Delta9), using an inducible renal epithelial-specific system. Endogenous CUL3 was reduced to 50% in both models, and consistent with autoubiquitination, CUL3-Delta9 protein was undetectable in CUL3-Het/Delta9 kidneys unless primary renal epithelia cells were cultured. Abundances of WNK4 and phosphorylated NCC did not differ between control and CUL3-Het mice, but they were elevated in CUL3-Het/Delta9 mice, which also displayed higher plasma [K+] and blood pressure. Abundance of phosphorylated Na+-K+-2Cl- cotransporter (NKCC2) was also increased, which may contribute to the severity of CUL3-Delta9-mediated FHHt. WNK4 and SPAK localized to puncta in NCC-positive segments but not in NKCC2-positive segments, suggesting differential effects of CUL3-Delta9. These results indicate that Cul3 haploinsufficiency does not cause FHHt, but dominant effects of CUL3-Delta9 are required. |Animals[MESH] |Blood Pressure/genetics[MESH] |Cells, Cultured[MESH] |Cullin Proteins/*genetics/*metabolism[MESH] |Epithelial Cells[MESH] |Female[MESH] |Haploinsufficiency[MESH] |Heterozygote[MESH] |Kidney/metabolism[MESH] |Male[MESH] |Mice[MESH] |Mutation[MESH] |Phosphorylation[MESH] |Potassium/blood[MESH] |Protein Serine-Threonine Kinases/metabolism[MESH] |Pseudohypoaldosteronism/*genetics/*metabolism/physiopathology[MESH] |Solute Carrier Family 12, Member 1/metabolism[MESH] |Solute Carrier Family 12, Member 3/metabolism[MESH] |Ubiquitination[MESH]Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant(epmc).pdf DeepDyve Pubget Overpricing