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Plekha7, a candidate gene for human hypertension, plays a critical role in the regulation of intracellular calcium
Author(s) -
Endres Bradley,
Priestley Jessica RC,
Palygin Oleg,
Hoffman Matthew,
Moreno Carol,
Lombard Julian,
Jacob Howard J,
Geurts Aron M
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.955.2
Subject(s) - intracellular , medicine , endocrinology , mutant , extracellular , blood pressure , chemistry , calcium in biology , phenylephrine , biology , gene , biochemistry
Plekha7 (Plekstrin homology domain containing family A member 7) has been identified by numerous genetic studies as a candidate gene for human hypertension. We disrupted Plekha7 in the SS rat by Zinc‐Finger Nuclease (ZFN) mutagenesis in order to investigate its role in blood pressure control. Four weeks on a high salt diet (8% NaCl) produced no changes in blood pressure between mutant and wild‐type (WT) littermates, although mutants demonstrated improved renal phenotypes (reduced proteinuria, protein casting, glomerulosclerosis, and fibrosis). We hypothesized that these differences were caused by vascular changes in the Plekha7 mutants. Resistance arteries from these mutants were less responsive to dilators acetylcholine (logEC 50 of −6.01±0.17 vs. − 6.66±0.12, p≤0.05) and nitroprusside (logEC 50 of −7.19±0.14 vs. − 7.66±0.13, p≤0.05) but showed no difference in contractile response to phenylephrine (PE) or endothelin‐1. In Ca 2+ ‐free buffer, vessels contracted more to 10 μM PE (32.44±2.08% vs. 15.58±2.89%, p≤0.05), indicating an elevation in intracellular Ca 2+ content. In isolated glomeruli, there was an amplified intracellular Ca 2+ response to high extracellular Ca 2+ . These data indicate that despite a lack of evidence for controlling blood pressure in the SS rat, Plekha7 plays an integral role in vascular function through regulation of intracellular Ca 2+ .