Targeted disruption of Adamts16 gene in a rat genetic model of hypertension

Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20555-9. doi: 10.1073/pnas.1211290109. Epub 2012 Nov 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / deficiency
  • ADAM Proteins / genetics*
  • ADAM Proteins / physiology*
  • Animals
  • Base Sequence
  • Blood Pressure / genetics
  • Blood Pressure / physiology
  • Blood Vessels / pathology
  • Blood Vessels / physiopathology
  • DNA / genetics
  • Disease Models, Animal
  • Female
  • Gene Targeting
  • Heterozygote
  • Homozygote
  • Hypertension / genetics*
  • Hypertension / pathology
  • Hypertension / physiopathology*
  • Kidney Glomerulus / blood supply
  • Kidney Glomerulus / pathology
  • Male
  • Mutant Proteins / genetics
  • Mutant Proteins / physiology
  • Pulse Wave Analysis
  • Rats
  • Rats, Inbred Dahl
  • Rats, Mutant Strains
  • Sequence Deletion
  • Tunica Media / pathology


  • Mutant Proteins
  • DNA
  • ADAM Proteins