Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation
Mohamed A. Saleh, … , David G. Harrison, Meena S. Madhur
Mohamed A. Saleh, … , David G. Harrison, Meena S. Madhur
Published February 9, 2015
Citation Information: J Clin Invest. 2015;125(3):1189-1202. https://doi.org/10.1172/JCI76327.
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Research Article Nephrology

Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation

Abstract

The lymphocyte adaptor protein LNK (also known as SH2B3) is primarily expressed in hematopoietic and endothelial cells, where it functions as a negative regulator of cytokine signaling and cell proliferation. Single-nucleotide polymorphisms in the gene encoding LNK are associated with autoimmune and cardiovascular disorders; however, it is not known how LNK contributes to hypertension. Here, we determined that loss of LNK exacerbates angiotensin II–induced (Ang II–induced) hypertension and the associated renal and vascular dysfunction. At baseline, kidneys from Lnk–/– mice exhibited greater levels of inflammation, oxidative stress, and glomerular injury compared with WT animals, and these parameters were further exacerbated by Ang II infusion. Aortas from Lnk–/– mice exhibited enhanced inflammation, reduced nitric oxide levels, and impaired endothelial-dependent relaxation. Bone marrow transplantation studies demonstrated that loss of LNK in hematopoietic cells is primarily responsible for the observed renal and vascular inflammation and predisposition to hypertension. Ang II infusion increased IFN-γ–producing CD8+ T cells in the spleen and kidneys of Lnk–/– mice compared with WT mice. Moreover, IFN-γ deficiency resulted in blunted hypertension in response to Ang II infusion. Together, these results suggest that LNK is a potential therapeutic target for hypertension and its associated renal and vascular sequela.

Authors

Mohamed A. Saleh, William G. McMaster, Jing Wu, Allison E. Norlander, Samuel A. Funt, Salim R. Thabet, Annet Kirabo, Liang Xiao, Wei Chen, Hana A. Itani, Danielle Michell, Tianxiao Huan, Yahua Zhang, Satoshi Takaki, Jens Titze, Daniel Levy, David G. Harrison, Meena S. Madhur

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Figure 4

Loss of LNK promotes renal oxidative stress and glomerular injury.

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Loss of LNK promotes renal oxidative stress and glomerular injury. WT an...
WT and Lnk–/– mice were infused with vehicle (sham) or Ang II (490 ng/kg/min) for 2 weeks. Quantitative analysis of superoxide levels, as detected by 2-hydroxyethidium, in renal cortex (A) and medulla (B). n = 9 per group. (C) Representative micrographs of DHE staining in kidney (n = 3 per group). Glomerular filtration barrier injury was assessed by quantifying 24-hour urinary excretion of albumin (D) and nephrin (E). n = 6 per group. Renal tubular damage was evaluated by measuring total kidney mRNA NGAL expression (F) (n = 4–5 per group) and 24-hour urinary NGAL excretion (G) (n = 7 per group). Renal function was assessed by injecting mice intraperitoneally with a saline load equal to 10% body weight and determining urine volume (H) and sodium excretion (I) over the ensuing 4 hours using a metabolic chamber (n = 7–8 per group). Data are expressed as mean ± SEM. P values for the effect of Ang II, the effect of Lnk deficiency, and the interaction of Ang II and genotype as calculated by 2-way ANOVA are shown for A, B, and D–G. *P < 0.05; ****P < 0.0001 vs. WT/Ang II. For H and I, unpaired Student’s 1-tailed t test was used. **P < 0.01 vs. WT.