title: Af17 deficiency increases sodium excretion and decreases blood pressure.
abstract: The putative transcription factor AF17 upregulates the transcription of the epithelial sodium channel (ENaC) genes, but whether AF17 modulates sodium homeostasis and BP is unknown. Here, we generated Af17-deficient mice to determine whether deletion of Af17 leads to sodium wasting and low BP. Compared with wild-type mice, Af17-deficient mice had lower BP (11 mmHg), higher urine volume, and increased sodium excretion despite mildly increased plasma concentrations of aldosterone. Deletion of Af17 led to increased dimethylation of histone H3 K79 and reduced ENaC function. The attenuated function of ENaC resulted from decreased ENaC mRNA and protein expression, fewer active channels, lower open probability, and reduced effective activity. In contrast, inducing high levels of plasma aldosterone by a variety of methods completely compensated for Af17 deficiency with respect to sodium handling and BP. Taken together, these data identify Af17 as a potential locus for the maintenance of sodium and BP homeostasis and suggest that a particular histone modification is directly linked to these processes. Af17-mediated regulation of BP is largely, but not exclusively, the result of modulating ENaC, suggesting it has potential as a therapeutic target for the control of BP.
authors.affiliation: Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Lihe
authors.initials: L
authors.lastname: Chen
authors.forename: Hongyu
authors.initials: H
authors.lastname: Wu
authors.forename: Oleh M
authors.initials: OM
authors.lastname: Pochynyuk
authors.forename: Mary Rose
authors.initials: MR
authors.lastname: Reisenauer
authors.forename: Zhijing
authors.initials: Z
authors.lastname: Zhang
authors.forename: Le
authors.initials: L
authors.lastname: Huang
authors.forename: Oleg Leonidovych
authors.initials: OL
authors.lastname: Zaika
authors.forename: Mykola
authors.initials: M
authors.lastname: Mamenko
authors.forename: Weiru
authors.initials: W
authors.lastname: Zhang
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Zhou
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D053503:Epithelial Sodium Channels / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D017419:Potassium, Dietary / Q000494:pharmacology; D012964:Sodium / Q000652:urine*; D012982:Sodium, Dietary / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D053503:Epithelial Sodium Channels; D006657:Histones; C486273:Mllt6 protein, mouse; D009363:Neoplasm Proteins; D017419:Potassium, Dietary; D012982:Sodium, Dietary; D000450:Aldosterone; D012964:Sodium