Mutation of SH2B3 (LNK), a genome-wide association study candidate for hypertension, attenuates dahl salt-sensitive hypertension via inflammatory modulation

Nathan P. Rudemiller, Hayley Lund, Jessica R.C. Priestley, Bradley T. Endres, Jeremy W. Prokop, Howard J. Jacob, Aron M. Geurts, Eric P. Cohen, David L. Mattson

Research output: Contribution to journalArticle

Abstract

Human genome-wide association studies have linked SH2B adaptor protein 3 (SH2B3, LNK) to hypertension and renal disease, although little experimental investigation has been performed to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases. The resulting mutation was a 6-bp, in-frame deletion within a highly conserved region of the Src homology 2 (SH2) domain of SH2B3. This mutation significantly attenuated Dahl SS hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the Sh2b3em1Mcwi mutant rats. To determine whether this was because of differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and Sh2b3em1Mcwi mutants underwent total body irradiation and were then transplanted with Dahl SS or Sh2b3em1Mcwi mutant bone marrow. Rats that received Sh2b3em1Mcwi mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease.

Original languageEnglish (US)
Pages (from-to)1111-1117
Number of pages7
JournalHypertension
Volume65
Issue number5
DOIs
StatePublished - May 21 2015
Externally publishedYes

Fingerprint

Genome-Wide Association Study
Salts
Renal Hypertension
Hypertension
Mutation
Bone Marrow
Inbred Dahl Rats
Pathology
Kidney
Proteins
src Homology Domains
Whole-Body Irradiation
Zinc Fingers
Human Genome
Cerebral Palsy
Immune System
Arterial Pressure
Leukocytes
Diet
Transplants

Keywords

  • hypertension
  • immune system
  • kidney
  • lymphocytes
  • rats

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Mutation of SH2B3 (LNK), a genome-wide association study candidate for hypertension, attenuates dahl salt-sensitive hypertension via inflammatory modulation. / Rudemiller, Nathan P.; Lund, Hayley; Priestley, Jessica R.C.; Endres, Bradley T.; Prokop, Jeremy W.; Jacob, Howard J.; Geurts, Aron M.; Cohen, Eric P.; Mattson, David L.

In: Hypertension, Vol. 65, No. 5, 21.05.2015, p. 1111-1117.

Research output: Contribution to journalArticle

Rudemiller, NP, Lund, H, Priestley, JRC, Endres, BT, Prokop, JW, Jacob, HJ, Geurts, AM, Cohen, EP & Mattson, DL 2015, 'Mutation of SH2B3 (LNK), a genome-wide association study candidate for hypertension, attenuates dahl salt-sensitive hypertension via inflammatory modulation', Hypertension, vol. 65, no. 5, pp. 1111-1117. https://doi.org/10.1161/HYPERTENSIONAHA.114.04736
Rudemiller, Nathan P. ; Lund, Hayley ; Priestley, Jessica R.C. ; Endres, Bradley T. ; Prokop, Jeremy W. ; Jacob, Howard J. ; Geurts, Aron M. ; Cohen, Eric P. ; Mattson, David L. / Mutation of SH2B3 (LNK), a genome-wide association study candidate for hypertension, attenuates dahl salt-sensitive hypertension via inflammatory modulation. In: Hypertension. 2015 ; Vol. 65, No. 5. pp. 1111-1117.
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