Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation
Saleh MA, Mcmaster WG, Wu J, Norlander AE, Funt SA, Thabet SR, Kirabo A, Xiao L, Chen W, Itani HA, Michell D, Huan T, Zhang Y, Takaki S, Titze J, Levy D, Harrison DG, Madhur MS (2015)
Publication Type: Journal article
Publication year: 2015
Journal
Book Volume: 125
Pages Range: 1189-202
Journal Issue: 3
DOI: 10.1172/JCI76327
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-?-producing CD8+ T cells in the spleen and kidneys of Lnk-/- mice compared with WT mice. Moreover, IFN-? 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 with CRIS profile
Involved external institutions
Vanderbilt University
United States (USA) (US)
US National Institutes of Health (NIH)
United States (USA) (US)
National Center for Global Health and Medicine (NCGM)
Japan (JP)
Emory University
United States (USA) (US)
United States (USA) (US)
US National Institutes of Health (NIH)
United States (USA) (US)
National Center for Global Health and Medicine (NCGM)
Japan (JP)
Emory University
United States (USA) (US)
How to cite
APA:
Saleh, M.A., Mcmaster, W.G., Wu, J., Norlander, A.E., Funt, S.A., Thabet, S.R.,... Madhur, M.S. (2015). Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation. Journal of Clinical Investigation, 125(3), 1189-202. https://doi.org/10.1172/JCI76327
MLA:
Saleh, Mohamed A., et al. "Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation." Journal of Clinical Investigation 125.3 (2015): 1189-202.
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