Linking inflammation and hypertension via LNK/SH2B3

Abstract

Purpose of review: Hypertension is a leading cause of cardiovascular and renal morbidity, and mortality. Genome-wide association studies identified a single-nucleotide polymorphism in the gene SH2B3 encoding the lymphocyte adaptor protein, LNK, but, until recently, little was known about how LNK contributes to hypertension. This review summarizes recent work highlighting a central role for LNK in inflammation and hypertension.

Recent findings: Using a systems biology approach that integrates genomic data with whole blood transcriptomic data and network modeling, LNK/SH2B3 was identified as a key driver gene for hypertension in humans. LNK is an intracellular adaptor protein expressed predominantly in hematopoietic and endothelial cells that negatively regulates cell proliferation and cytokine signaling. Genetic animal models with deletion or mutation of LNK revealed an important role for LNK in renal and vascular inflammation, glomerular injury, oxidative stress, interferon-γ production, and hypertension. Bone marrow transplantation experiments revealed that LNK in hematopoietic cells is primarily responsible for blood pressure regulation.

Summary: LNK/SH2B3 is a key driver gene for human hypertension, and alteration of LNK in animal models has a profound effect on inflammation and hypertension. Thus, LNK is a potential therapeutic target for this disease and its devastating consequences.

Figure 1

Schematic diagram of the structural organization of LNK/SH2B3 showing the location of the GWAS identified single nucleotide polymorphism (SNP rs3184504), leading to an arginine to tryptophan substitution at amino acid 262 (R262W) and the 6 bp in frame deletion created by Rudemiller et al [**17]. PH: Pleckstrin homology domain; SH2: Src homology 2 domain.

Figure 2

Proposed model for how LNK deficiency exacerbates hypertension and end-organ dysfunction. Loss of LNK in dendritic cells (DC) promotes polarization of naïve T cells into IFNγ producing Th1/Tc1 cells rather than the anti-inflammatory T regulatory (T reg) cells. LNK deficiency results in increased accumulation of Th1/Tc1 cells in organs such as the kidney and blood vessel. Increased inflammation and IFNγ production lead to increased sodium reabsorption, superoxide production, and albuminuria in the kidney and decreased nitric oxide and impaired endothelial dependent relaxation in vessels and ultimately hypertension.