title: Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat.
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.
authors.affiliation: Departments of Physiology and Human and Molecular Genetics Center, and.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Endres
authors.affiliation: Departments of Physiology and.
authors.forename: Jessica R C
authors.initials: JR
authors.lastname: Priestley
authors.affiliation: Departments of Physiology and.
authors.forename: Oleg
authors.initials: O
authors.lastname: Palygin
authors.affiliation: Departments of Physiology and Human and Molecular Genetics Center, and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Flister
authors.affiliation: Departments of Physiology and.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hoffman
authors.affiliation: Departments of Physiology and.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Weinberg
authors.affiliation: Departments of Physiology and Human and Molecular Genetics Center, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Grzybowski
authors.affiliation: Departments of Physiology and.
authors.forename: Julian H
authors.initials: JH
authors.lastname: Lombard
authors.affiliation: Departments of Physiology and.
authors.forename: Alexander
authors.identifier: http://orcid.org/0000-0002-5190-8356
authors.initials: A
authors.lastname: Staruschenko
authors.affiliation: Departments of Physiology and Human and Molecular Genetics Center, and.
authors.forename: Carol
authors.initials: C
authors.lastname: Moreno
authors.affiliation: Departments of Physiology and Human and Molecular Genetics Center, and Pediatrics.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.affiliation: Departments of Physiology and Human and Molecular Genetics Center, and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226 ageurts@mcw.edu.
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000235:genetics* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002302:Cardiac Output / Q000235:genetics / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D055106:Genome-Wide Association Study; D006977:Hypertension, Renal / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008638:Mesenteric Arteries / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D011922:Rats, Mutant Strains; D012965:Sodium Chloride / Q000494:pharmacology*; D014655:Vascular Resistance / Q000235:genetics / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C000592939:Plekha7 protein, rat; D009569:Nitric Oxide; D012965:Sodium Chloride; D002118:Calcium
keywords: GWAS; adherens junction; endothelial cells; genetic; physiology