RGD Reference Report - Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat. - Rat Genome Database

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Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat.

Authors: Endres, BT  Priestley, JR  Palygin, O  Flister, MJ  Hoffman, MJ  Weinberg, BD  Grzybowski, M  Lombard, JH  Staruschenko, A  Moreno, C  Jacob, HJ  Geurts, AM 
Citation: Endres BT, etal., Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12817-22. doi: 10.1073/pnas.1410745111. Epub 2014 Aug 18.
RGD ID: 11079199
Pubmed: PMID:25136115   (View Abstract at PubMed)
PMCID: PMC4156702   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1410745111   (Journal Full-text)

PLEKHA7 (pleckstrin homology domain containing family A member 7) has been found in multiple studies as a candidate gene for human hypertension, yet functional data supporting this association are lacking. We investigated the contribution of this gene to the pathogenesis of salt-sensitive hypertension by mutating Plekha7 in the Dahl salt-sensitive (SS/JrHsdMcwi) rat using zinc-finger nuclease technology. After four weeks on an 8% NaCl diet, homozygous mutant rats had lower mean arterial (149 +/- 9 mmHg vs. 178 +/- 7 mmHg; P < 0.05) and systolic (180 +/- 7 mmHg vs. 213 +/- 8 mmHg; P < 0.05) blood pressure compared with WT littermates. Albumin and protein excretion rates were also significantly lower in mutant rats, demonstrating a renoprotective effect of the mutation. Total peripheral resistance and perivascular fibrosis in the heart and kidney were significantly reduced in Plekha7 mutant animals, suggesting a potential role of the vasculature in the attenuation of hypertension. Indeed, both flow-mediated dilation and endothelium-dependent vasodilation in response to acetylcholine were improved in isolated mesenteric resistance arteries of Plekha7 mutant rats compared with WT. These vascular improvements were correlated with changes in intracellular calcium handling, resulting in increased nitric oxide bioavailability in mutant vessels. Collectively, these data provide the first functional evidence that Plekha7 may contribute to blood pressure regulation and cardiovascular function through its effects on the vasculature.



Disease Annotations    
Cardiac Fibrosis  (IMP,ISO)
glomerulosclerosis  (IMP,ISO)
hypertension  (IMP,ISO)

Gene Ontology Annotations    

Biological Process
vasodilation  (IMP)

Phenotype Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Plekha7  (pleckstrin homology domain containing A7)
Plekha7em4Mcwi  (pleckstrin homology domain containing, family A member 7; zinc finger nuclease induced mutant 4, Medical College of Wisconsin)

Genes (Mus musculus)
Plekha7  (pleckstrin homology domain containing, family A member 7)

Genes (Homo sapiens)
PLEKHA7  (pleckstrin homology domain containing A7)

Strains
SS-Plekha7em4Mcwi-/-  (SS-Plekha7em4Mcwi-/Plekha7em4Mcwi-)

Objects referenced in this article
Strain SS-Plekha7em4Mcwi null Rattus norvegicus

Additional Information