A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage

Abstract

Rationale: SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single-nucleotide polymorphism in SH2B3 (rs3184504) results in substitution of tryptophan for arginine at amino acid 262 and is a top association signal for hypertension in human genome-wide association studies. Whether this variant is causal for hypertension, and if so, the mechanism by which it impacts pathogenesis is unknown. Objectives: Test the hypothesis that the tryptophan-encoding allele of rs3184504 promotes hypertension development and end-organ damage through loss of SH2B3-mediated repression of cytokine signaling to enhance T-cell activation. Methods and Results: We used CRISPR-Cas9 technology to create mice homozygous for the major (arginine/arginine) and minor (tryptophan/tryptophan) alleles of this SH2B3 polymorphism. Tryptophan/tryptophan mice exhibited 10 mm Hg higher systolic blood pressure during chronic Ang II (angiotensin II) infusion compared with arginine/arginine controls. Renal injury and perivascular fibrosis were exacerbated in tryptophan/tryptophan mice compared with arginine/arginine controls following Ang II infusion. In addition, renal and ex vivo stimulated splenic CD8 + T cells from Ang II–infused tryptophan/tryptophan mice produced significantly more IFN (interferon)-γ compared with arginine/arginine controls. IL (Interleukin)-12-induced IFN-γ production was greater in tryptophan/tryptophan compared with arginine/arginine CD8 + T cells. In addition, IL-12 enhanced Stat4 (signal transducer and activator of transcription 4) phosphorylation to a greater degree in tryptophan/tryptophan compared with arginine/arginine CD8 + T cells, suggesting that tryptophan-encoding SH2B3 exhibits less negative regulation of IL-12 signaling to promote IFN-γ production. Finally, we demonstrated that a multi-single-nucleotide polymorphism model genetically predicting increased SH2B3 expression in lymphocytes is inversely associated with hypertension and hypertensive chronic kidney disease in humans. Conclusions: Taken together, these results suggest that the tryptophan-encoding allele of rs3184504 is causal for blood pressure elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T-cell IL-12 signaling leading to enhanced IFN-γ production.

Modulating T Cell Phenotype and Function to Treat Hypertension

“…These findings suggest that the rs3184504 minor allele is a causal variant for hypertension through at least a partial loss of function of Sh2b3 resulting in enhanced T-cell IFNg production. 40 Although Mori et al demonstrated that Sh2b3 deficiency can have cell intrinsic effects in both DCs and T cells to promote IFNg production, 41 we did not find significant differences in dendritic and other myeloid cell cytokine production in mice with the Sh2b3 minor versus major alleles. 40 Hence, it seems that Sh2b3 plays a particularly key role in limiting T-cell activation and cytokine production in hypertension.…”

“…Alternative approaches include inhibiting Jak-Stat signaling to limit T-cell activation, particularly Stat4, which promotes enhanced IFNg expression and is activated to a greater degree in T cells harboring the SH2B3 minor allele. 42 This approach may be particularly efficacious in those of European ancestry who have a minor allele frequency for this variant of . 40%.…”

“…Alternative approaches include inhibiting Jak-Stat signaling to limit T-cell activation, particularly Stat4, which promotes enhanced IFN γ expression and is activated to a greater degree in T cells harboring the SH2B3 minor allele. 42 This approach may be particularly efficacious in those of European ancestry who have a minor allele frequency for this variant of > 40%. 43 Given that the SH2B3 rs3184504 polymorphism is also associated with a variety of autoimmune diseases, including type 1 diabetes mellitus, 44 rheumatoid arthritis, 45 and celiac disease, 46 identifying whether SH2B3 alters T-cell cytokine signaling in these conditions may also lead to new therapeutic approaches.…”

The link between immunity and hypertension in the kidney and heart

“…Targeting the immune system to lower blood pressure and reduce organ damage has proven complicated ( 201 , 202 ), but organ specific immune targeting using nanotechnology appears to be a promising solution to reduce toxicities ( 155 , 199 ). Recent identification of single nucleotide polymorphisms in SH2B adaptor protein 3 contributing to T cell involvement in hypertension and renal damage ( 203 ) further complicates therapeutic targeting as genetic mutations may predispose certain immune cells to promote inflammation, supporting consideration of individual patient genetic predispositions when identifying driving factors of hypertension to design future treatment plans, as is becoming increasingly debated ( 204 ). As contributing immune players and inflammation-mediating molecules are characterized, novel pathways can be identified and targeted therapeutically to lower blood pressure and attenuate hypertension-mediated organ dysfunction.…”

Interferon gamma in the pathogenesis of hypertension − recent insights

“…Additional prudence, then, is warranted when discussing IFNγ-related mechanisms. Several recent preclinical studies have continued to uncover the molecular mechanisms by which IFNγ mediates the progression of cardiovascular diseases [ 6 ▪ , 24 ▪ , 29 ▪▪ , 30 ▪▪ , 31 ▪ , 32 ▪ ], and several recent clinical studies corroborate, at minimum, a correlation between IFNγ and elevated systolic blood pressure [ 33 ▪ , 34 ▪▪ , 35 ▪ ]. This review will highlight these recent findings from the last two years and discuss them in the context of presently understood mechanisms.…”