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

Circ Res. 2022 Oct 14;131(9):731-747. doi: 10.1161/CIRCRESAHA.121.320625. Epub 2022 Sep 28.

Abstract

Background: 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 (Trp) for arginine (Arg) 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.

Methods: We used CRISPR-Cas9 technology to create mice homozygous for the major (Arg/Arg) and minor (Trp/Trp) alleles of this SH2B3 polymorphism. Mice underwent angiotensin II (Ang II) infusion to evaluate differences in blood pressure (BP) elevation and end-organ damage including albuminuria and renal fibrosis. Cytokine production and Stat4 phosphorylation was also assessed in Arg/Arg and Trp/Trp T cells.

Results: Trp/Trp mice exhibit 10 mmHg higher systolic BP during chronic Ang II infusion compared to Arg/Arg controls. Renal injury and perivascular fibrosis are exacerbated in Trp/Trp mice compared to Arg/Arg controls following Ang II infusion. Renal and ex vivo stimulated splenic CD8+ T cells from Ang II-infused Trp/Trp mice produce significantly more interferon gamma (IFNg) compared to Arg/Arg controls. Interleukin-12 (IL-12)-induced IFNg production is greater in Trp/Trp compared to Arg/Arg CD8+ T cells. In addition, IL-12 enhances Stat4 phosphorylation to a greater degree in Trp/Trp compared to Arg/Arg CD8+ T cells, suggesting that Trp-encoding SH2B3 exhibits less negative regulation of IL-12 signaling to promote IFNg production. Finally, we demonstrated that a multi-SNP 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 Trp encoding allele of rs3184504 is causal for BP elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T cell IL-12 signaling leading to enhanced IFNg production.

Keywords: cytokines; hypertension; inflammation; lymphocytes; polymorphism, single nucleotide.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Angiotensin II / metabolism
  • Angiotensin II / toxicity
  • Animals
  • Arginine / adverse effects
  • Arginine / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Fibrosis
  • Genome-Wide Association Study
  • Humans
  • Hypertension* / metabolism
  • Hypertension, Renal* / metabolism
  • Interferon-gamma / metabolism
  • Interleukin-12 / adverse effects
  • Interleukin-12 / metabolism
  • Kidney / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polymorphism, Single Nucleotide
  • Tryptophan

Substances

  • Adaptor Proteins, Signal Transducing
  • Lnk protein, mouse
  • Angiotensin II
  • Interleukin-12
  • Interferon-gamma
  • Tryptophan
  • Arginine