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Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat. Proc Natl Acad Sci U S A 2014 Sep 02;111(35):12817-22

Date

08/20/2014

Pubmed ID

25136115

Pubmed Central ID

PMC4156702

DOI

10.1073/pnas.1410745111

Scopus ID

2-s2.0-84907228029   26 Citations

Abstract

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.

Author List

Endres BT, Priestley JR, Palygin O, Flister MJ, Hoffman MJ, Weinberg BD, Grzybowski M, Lombard JH, Staruschenko A, Moreno C, Jacob HJ, Geurts AM

Authors

Aron Geurts PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Julian H. Lombard PhD Professor in the Physiology department at Medical College of Wisconsin
Oleg Palygin PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Alexander V. Staruschenko PhD Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Albuminuria
Animals
Blood Pressure
Calcium
Cardiac Output
Carrier Proteins
Disease Models, Animal
Endothelial Cells
Genome-Wide Association Study
Hypertension, Renal
Mesenteric Arteries
Nitric Oxide
Rats
Rats, Inbred Dahl
Rats, Mutant Strains
Sodium Chloride
Vascular Resistance
jenkins-FCD Prod-398 336d56a365602aa89dcc112f077233607d6a5abc