title: Targeted disruption of Adamts16 gene in a rat genetic model of hypertension.
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 Adamts16(mutant) rats was lower by 36 mmHg compared with the BP of the S rats. The Adamts16(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, Adamts16(mutant) 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.
authors.affiliation: Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
authors.forename: Kathirvel
authors.initials: K
authors.lastname: Gopalakrishnan
authors.forename: Sivarajan
authors.initials: S
authors.lastname: Kumarasamy
authors.forename: Shakila
authors.initials: S
authors.lastname: Abdul-Majeed
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Kalinoski
authors.forename: Eric E
authors.initials: EE
authors.lastname: Morgan
authors.forename: Amira F
authors.initials: AF
authors.lastname: Gohara
authors.forename: Surya M
authors.initials: SM
authors.lastname: Nauli
authors.forename: Wanda E
authors.initials: WE
authors.lastname: Filipiak
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Saunders
authors.forename: Bina
authors.initials: B
authors.lastname: Joe
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D001808:Blood Vessels / Q000473:pathology / Q000503:physiopathology; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D006579:Heterozygote; D006720:Homozygote; D006973:Hypertension / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000473:pathology; D008297:Male; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D063177:Pulse Wave Analysis; D051381:Rats; D020303:Rats, Inbred Dahl; D011922:Rats, Mutant Strains; D017384:Sequence Deletion; D017540:Tunica Media / Q000473:pathology
chemical_list: D050505:Mutant Proteins; D004247:DNA; D051722:ADAM Proteins