Mutation of SH2B3 (LNK), a Genome-Wide Association Study Candidate for Hypertension, Attenuates Dahl Salt-Sensitive Hypertension via Inflammatory Modulation. Issue 5 (May 2015)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Hypertension. Volume 65:Issue 5(2015:May)
• Publication Date: 2015-05
• Subjects: Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.114.04736
• Languages: English
• ISSNs: 0194-911X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p>Human genome-wide association studies have linked SH2B adaptor protein 3 (<italic>SH2B3</italic>, <italic>LNK</italic>) to hypertension and renal disease, although little experimental investigation has been performed to verify a role for <italic>SH2B3</italic> 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 <italic>SH2B3</italic> and hypertension, we targeted the <italic>SH2B3</italic> 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 <italic>SH2B3</italic>. 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 Sh2b3<sup>em1Mcwi</sup> mutant rats. To determine whether this was because of differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and Sh2b3<sup>em1Mcwi</sup> mutants underwent total body irradiation and were then transplanted with Dahl SS or Sh2b3<sup>em1Mcwi</sup> mutant bone marrow. Rats that received Sh2b3<sup>em1Mcwi</sup> 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.</p> </sec> </abstract>