Abstract 006: Mutation of SH2B3, a GWAS Candidate Gene for Hypertension, Attenuates Dahl SS Pathology

Abstract

The immune system mediates hypertension in many experimental models, though the mechanisms remain unclear. In the Dahl salt-sensitive (SS) rat, infiltration of T lymphocytes and macrophages in the kidneys parallels the onset of hypertension and renal disease in response to high salt diet (4% NaCl). Immunosuppressive treatment blunts the infiltration of immune cells in the kidneys and attenuates the hypertensive pathology. SH2B3, a gene associated with human hypertension in many GWAS, encodes an intracellular adaptor protein shown to play an important role in inflammatory signaling. Mutation of SH2B3 via zinc-finger nucleases on the Dahl SS genetic background reduces immune cell infiltration in the kidneys and significantly attenuates the hypertensive pathology. Bone marrow transplant studies (n=5-6/group; below) show that Dahl SS or SH2B3 mutant rats receiving the SH2B3 mutant bone marrow (open circles, light bars) have significantly attenuated hypertension and albuminuria compared to rats receiving the Dahl SS bone marrow (closed circles, dark bars; * indicates P<0.05 vs. final day of 0.4% NaCl, † indicates P<0.05 vs. Dahl SS on the same day). These studies indicate a role for the immune system in the altered phenotype in the SH2B3 mutant rat. One possible immune mechanism involved is interleukin 6 (IL-6) signaling, a proinflammatory pathway in which SH2B3 functions. After 21 days on 4% NaCl diet (n=5-6/group), SH2B3 mutants have significantly lower mRNA expression of IL-6 (expressed as fold change of Dahl SS) in the renal cortex (0.54, p<0.05) and renal medulla (0.45, p<0.05). Further studies of IL-6 signaling will elucidate its role in Dahl SS hypertension.