Targeted disruption of Adamts16 gene in a rat genetic model of hypertension
Open Access
- 26 November 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (50), 20555-20559
- https://doi.org/10.1073/pnas.1211290109
Abstract
A disintegrin-like metalloproteinase with thrombospondin motifs–16 (Adamts16) is an important candidate gene for hypertension. The goal of the present study was to further assess the candidacy of Adamts16 by targeted disruption of this gene in a rat genetic model of hypertension. A rat model was generated by manipulating the genome of the Dahl Salt–sensitive (S) rat using zinc-finger nucleases, wherein the mutant rat had a 17 bp deletion in the first exon of Adamts16, introducing a stop codon in the transcript. Systolic blood pressure (BP) of the homozygous Adamts16mutant rats was lower by 36 mmHg compared with the BP of the S rats. The Adamts16mutant rats exhibited significantly lower aortic pulse wave velocity and vascular media thickness compared with S rats. Scanning electron and fluorescence microscopic studies indicated that the mechanosensory cilia of vascular endothelial cells from the Adamts16mutant rats were longer than that of the S rats. Furthermore, Adamts16mutant rats showed splitting and thickening of glomerular capillaries and had a longer survival rate, compared with the S rats. Taken together, these physiological observations functionally link Adamts16 to BP regulation and suggest the vasculature as the potential site of action of Adamts16 to lower BP.Keywords
This publication has 25 references indexed in Scilit:
- Increased Expression of NAD(P)H Oxidase Subunit p67phox in the Renal Medulla Contributes to Excess Oxidative Stress and Salt-Sensitive HypertensionCell Metabolism, 2012
- Refined mapping of blood pressure quantitative trait loci using congenic strains developed from two genetically hypertensive rat modelsHypertension Research, 2011
- Dopamine Receptor Type 5 in the Primary Cilia Has Dual Chemo- and Mechano-Sensory RolesHypertension, 2011
- Augmented Rififylin Is a Risk Factor Linked to Aberrant Cardiomyocyte Function, Short-QT Interval and HypertensionHypertension, 2011
- Knockout Rats via Embryo Microinjection of Zinc-Finger NucleasesScience, 2009
- Positional identification of variants of Adamts16 linked to inherited hypertensionHuman Molecular Genetics, 2009
- Advances in transgenic rat productionTransgenic Research, 2006
- Linkage analysis of neointimal hyperplasia and vascular wall transformation after balloon angioplastyPhysiological Genomics, 2006
- Isolation, Characterization, and Mapping of a Zinc Finger Gene, ZFP95, Containing Both a SCAN Box and an Alternatively Spliced KRAB A DomainGenomics, 1999
- Clinical value of aortic pulse-wave velocity measurementThe Lancet, 1999