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: Bradley T Endres, Jessica R C Priestley, Oleg Palygin, Michael J Flister, Matthew J Hoffman, Brian D Weinberg, Michael Grzybowski, Julian H Lombard, Alexander Staruschenko, Carol Moreno, Howard J Jacob, Aron M Geurts
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 35 Pg. 12817-22 (Sep 02 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25136115 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carrier Proteins
• Plekha7 protein, rat
• Nitric Oxide
• Sodium Chloride
• Calcium

Topics

• Albuminuria (genetics, pathology, physiopathology)
• Animals
• Blood Pressure (genetics, physiology)
• Calcium (metabolism)
• Cardiac Output (genetics, physiology)
• Carrier Proteins (genetics, physiology)
• Disease Models, Animal
• Endothelial Cells (physiology)
• Genome-Wide Association Study
• Hypertension, Renal (genetics, pathology, physiopathology)
• Mesenteric Arteries (physiology)
• Nitric Oxide (metabolism)
• Rats
• Rats, Inbred Dahl
• Rats, Mutant Strains
• Sodium Chloride (pharmacology)
• Vascular Resistance (genetics, physiology)