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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PLEKHA7HumanCardiac Fibrosis amelioratesISOPlekha7 (Rattus norvegicus)compared to wild typeRGD 
PLEKHA7HumanCardiac Fibrosis  ISOPlekha7 (Rattus norvegicus) RGD 
Plekha7RatCardiac Fibrosis amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7RatCardiac Fibrosis  IMP  RGD 
Plekha7MouseCardiac Fibrosis amelioratesISOPlekha7 (Rattus norvegicus)compared to wild typeRGD 
Plekha7MouseCardiac Fibrosis  ISOPlekha7 (Rattus norvegicus) RGD 
Plekha7em4McwiRatCardiac Fibrosis amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7em4McwiRatCardiac Fibrosis  IMP  RGD 
SS-Plekha7em4Mcwi-/-RatCardiac Fibrosis amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
PLEKHA7Humanglomerulosclerosis amelioratesISOPlekha7 (Rattus norvegicus)compared to wild typeRGD 
PLEKHA7Humanglomerulosclerosis  ISOPlekha7 (Rattus norvegicus) RGD 
Plekha7Ratglomerulosclerosis amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratglomerulosclerosis  IMP  RGD 
Plekha7Mouseglomerulosclerosis amelioratesISOPlekha7 (Rattus norvegicus)compared to wild typeRGD 
Plekha7Mouseglomerulosclerosis  ISOPlekha7 (Rattus norvegicus) RGD 
Plekha7em4McwiRatglomerulosclerosis amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7em4McwiRatglomerulosclerosis  IMP  RGD 
SS-Plekha7em4Mcwi-/-Ratglomerulosclerosis amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
PLEKHA7Humanhypertension amelioratesISOPlekha7 (Rattus norvegicus) RGD 
Plekha7Rathypertension amelioratesIMPcontrolled sodium chloride content diet RGD 
Plekha7Mousehypertension amelioratesISOPlekha7 (Rattus norvegicus) RGD 
Plekha7em4McwiRathypertension amelioratesIMPcontrolled sodium chloride content diet RGD 
SS-Plekha7em4Mcwi-/-Rathypertension amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Plekha7Ratvasodilation  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Plekha7Ratdecreased susceptibility to hypertension  IMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratdecreased susceptibility to hypertension  IMP  RGD 
Plekha7em4McwiRatdecreased susceptibility to hypertension  IMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7em4McwiRatdecreased susceptibility to hypertension  IMP  RGD 
SS-Plekha7em4Mcwi-/-Ratdecreased susceptibility to hypertension  IMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratdecreased systemic vascular resistance inducesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratdecreased systemic vascular resistance  IMP  RGD 
Plekha7em4McwiRatdecreased systemic vascular resistance inducesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7em4McwiRatdecreased systemic vascular resistance  IMP  RGD 
SS-Plekha7em4Mcwi-/-Ratdecreased systemic vascular resistance inducesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratdecreased urine albumin level amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratdecreased urine albumin level  IMP  RGD 
Plekha7em4McwiRatdecreased urine albumin level amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7em4McwiRatdecreased urine albumin level  IMP  RGD 
SS-Plekha7em4Mcwi-/-Ratdecreased urine albumin level amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratdecreased urine protein level amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratdecreased urine protein level  IMP  RGD 
Plekha7em4McwiRatdecreased urine protein level amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7em4McwiRatdecreased urine protein level  IMP  RGD 
SS-Plekha7em4Mcwi-/-Ratdecreased urine protein level amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratincreased cardiac output  IMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratincreased cardiac output  IMP  RGD 
Plekha7em4McwiRatincreased cardiac output  IMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7em4McwiRatincreased cardiac output  IMP  RGD 
SS-Plekha7em4Mcwi-/-Ratincreased cardiac output  IMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratincreased cardiac stroke volume inducesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratincreased cardiac stroke volume  IMP  RGD 
Plekha7em4McwiRatincreased cardiac stroke volume inducesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7em4McwiRatincreased cardiac stroke volume  IMP  RGD 
SS-Plekha7em4Mcwi-/-Ratincreased cardiac stroke volume inducesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7Ratincreased vasodilation  IMP compared to wild typeRGD 
Plekha7em4McwiRatincreased vasodilation  IMP compared to wild typeRGD 
SS-Plekha7em4Mcwi-/-Ratincreased vasodilation  IMP compared to wild typeRGD 
Plekha7Ratsalt-sensitive hypertension amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
Plekha7em4McwiRatsalt-sensitive hypertension amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 
SS-Plekha7em4Mcwi-/-Ratsalt-sensitive hypertension amelioratesIMPcontrolled sodium chloride content dietcompared to wild typeRGD 

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