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Hsd11b2 Targeting in the rat
Author(s) -
Mullins Linda Jane,
Peter Audrey,
Kenyon Christopher,
SourgiaKoutraki Yolanda,
Bailey Matthew,
Mullins John
Publication year - 2013
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.27.1_supplement.906.9
Subject(s) - circadian rhythm , medicine , endocrinology , microinjection , exon , biology , heart rate , allele , gene , blood pressure , genetics
We have used zinc finger nucleases (ZFNs) to target the rat Hsd11b2 gene by microinjection of ZFN mRNAs into single cell rat embryos. We generated multiple targeted alleles predicted to truncate the gene transcript. Having segregated the alleles by breeding, detailed metabolic and telemetric analyses of one line was undertaken. The Hsd2ZFNΔ120 line carries a 120bp deletion, removing half of exon 2. Animals homozygous for the deletion show symptoms of the syndrome of apparent mineralocorticoid excess (SAME). They are polydypsic and polyuric from an early age, but have increased haematocrit suggesting volume depletion. The increase in Na + /K + ratio on sodium loading (0.3% Na + to 3% Na + ) is blunted, compared to controls. Homozygotes are hypertensive on 0.3% Na + diet with a mean arterial blood pressure of 180mmHg (control MABP −115mmHg), and demonstrate a distinct lack of circadian rhythm (“non‐dippers”), though circadian rhythm for heart rate is normal. Sodium restriction (0.03% Na+) reduces BP to 140mmHg, but enhances its circadian rhythm. Meanwhile the concomitant tachycardia is sustained. We are currently investigating heart rate variability under different salt diet regimes. This rat model will extend experimental possibilities for exploring the mechanism underlying SAME.