Targeted disruption of Adamts 16 gene in a rat genetic model of hypertension

摘要

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 Adamts16~(mutant) rats was lower by 36 mmHg compared with the BP of the S rats. The Adamts 16~(mutant) 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 Adamts16~(mutant) rats were longer than that of the S rats. Furthermore, Adamts 16~(mutant) rats showed splitting and thickening of glo-merular 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 vascula-ture as the potential site of action of Adamts16 to lower BP.