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Expected hypotension in the Af17 knockout mouse
Author(s) -
Zhang Wenzheng
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1025.22
Subject(s) - epithelial sodium channel , downregulation and upregulation , homeostasis , knockout mouse , transcription factor , transcription (linguistics) , phenotype , endocrinology , microbiology and biotechnology , aldosterone , medicine , gene , biology , chemistry , sodium , genetics , linguistics , philosophy , organic chemistry
Our previous studies suggest that Dot1a‐Af9 complex represses the transcription of the epithelial Na + channel α subunit (α‐ENaC) gene by hypermethylating histone H3 K79 at the α‐ENaC promoter, that aldosterone treatment or Af17 overexpression relieves this repression by different mechanisms, and these transcriptional mechanisms are important in regulating ENaC‐mediated Na + transport. However, the significance of Af17 in regulating Na + homeostasis and thus blood pressure in vivo in mouse has not been tested. Accordingly, we hypothesize that deletion of Af17 leads to downregulation of ENaC transcription, ENaC activity and thus hypotension. To test this hypothesis, we generated Af17 −/− mice using gene trap ES cells in which Af17 was specifically disrupted. Af17 −/− mice are viable and have no obvious morphological or growth defects till 6 months old. However, compared to controls, Af17 −/− mice have a larger volume of urine and a lower blood pressure, regardless of the diet containing very low, low, normal or high amount of Na + . While control animals can tolerate high Na + (1%) in drinking water, Af17 −/− mice die from severe dehydration within 4 days of the treatment. Detailed characterization of the renal physiological phenotype and identification of the underlying molecular mechanisms are underway. Our data confirm and extend our previous findings regarding Dot1a‐Af9‐Af17 mediated regulation of ENaC transcription, ENaC activity, Na + transport and thus blood pressure, and highlight the importance of Af17 in these biological processes.