title: Synergistical effect of 20-HETE and high salt on NKCC2 protein and blood pressure via ubiquitin-proteasome pathway.
abstract: We previously generated a cytochrome P450 4F2 (CYP4F2) transgenic mouse model and demonstrated that overexpressed CYP4F2 and overproduced 20-HETE in the kidneys contribute to the increase of blood pressure in the CYP4F2 transgenic mice with normal salt intake. We currently expect to elucidate a potential mechanism of salt-related hypertension whereby diverse levels of 20-HETE interact with dietary salt on Na(+)-K(+)-2Cl(-) cotransporter, isoform 2 (NKCC2) in the kidneys of the transgenic and wild-type mice with high salt intake. High salt intake reduced about 85 % abundance of renal NKCC2 protein in the transgenic mice and about 24 % in the wild-type mice by Western blot. Furthermore, we first found that NKCC2 was ubiquitinated and interacted with Nedd4-2 by immunoprecipitation in the transgenic mice with high salt intake. In addition, inhibition of 20-HETE synthesis or proteasome activity reversed the reduction of NKCC2 expression induced by 20-HETE and high salt intake. These results suggest that 20-HETE and high salt intake synergistically decrease the expression of NKCC2 protein via Nedd4-2-mediated ubiquitin-proteasome pathway, and thereby modulate natriuresis and blood pressure. We propose that diverse levels of 20-HETE have diverse effects on blood pressure in different salt concentrations.
authors.affiliation: Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Liu
authors.forename: Guangrui
authors.initials: G
authors.lastname: Lai
authors.forename: Xianghong
authors.initials: X
authors.lastname: Yang
authors.forename: Luzeng
authors.initials: L
authors.lastname: Wang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D005786:Gene Expression Regulation; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000075702:Nedd4 Ubiquitin Protein Ligases; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012965:Sodium Chloride / Q000378:metabolism; D017673:Sodium Chloride, Dietary; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics* / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D006893:Hydroxyeicosatetraenoic Acids; D012333:RNA, Messenger; C578715:Slc12a1 protein, mouse; D017673:Sodium Chloride, Dietary; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D025801:Ubiquitin; D014662:Vasoconstrictor Agents; D012965:Sodium Chloride; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex