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Mutation of SH2B3 attenuates Dahl SS hypertension via inflammatory signaling (1136.15)
Author(s) -
Rudemiller Nathan,
Lund Hayley,
Priestley Jessica,
Geurts Aron,
Mattson David
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1136.15
Subject(s) - endocrinology , medicine , blood pressure , chemistry , kidney , inflammation
Previous studies implicate infiltrating immune cells in the kidney in the pathogenesis of Dahl salt sensitive hypertension. SH2B3, an adaptor protein shown to participate in vascular and inflammatory signaling, is associated with hypertension in human GWAS (Nature Gen 41:667), though the mechanisms underlying the association are unclear. To address this issue, zinc finger nuclease targeting of the SH2 domain of SH2B3 was performed in the Dahl SS rat (SS/JrHsdMcwi) and resulted in an in‐frame, 6 base pair deletion. Following salt stress, the SH2B3 mutants (SS‐Sh2b3 em1Mcwi ) had significantly lower blood pressure (135 ± 1 mmHg vs 168 ± 8 mmHg, n=4‐6/group) and attenuated kidney disease as indicated by albumin excretion rate (38 ± 7 mg/day vs 104 ± 9 mg/day) than the Dahl SS. Infiltration of leukocytes in the kidneys was significantly blunted in the SH2B3 mutant compared to the Dahl SS (5.4 ± 0.5 10 6 /kidney vs 2.7 ± 0.3 10 6 /kidney), and qPCR results show a significant reduction of IL‐6 (2 fold) and MCP‐1(1.8 fold) gene expression in the SH2B3 cortex. Vascular reactivity of mesenteric resistance arteries via wire myography in response serotonin or acetylcholine was not different between the SH2B3 mutant and Dahl SS. The mutation in SH2B3 appears to attenuate Dahl SS hypertension via inflammatory signaling and may reflect an underlying role for inflammation in human hypertension. Grant Funding Source : Supported by HL116264 and DK96859