title: 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
authors: MA
authors: Saleh
authors: William G
authors: WG
authors: McMaster
authors: Jing
authors: J
authors: Wu
authors: Allison E
authors: AE
authors: Norlander
authors: Samuel A
authors: SA
authors: Funt
authors: Salim R
authors: SR
authors: Thabet
authors: Annet
authors: A
authors: Kirabo
authors: Liang
authors: L
authors: Xiao
authors: Wei
authors: W
authors: Chen
authors: Hana A
authors: HA
authors: Itani
authors: Danielle
authors: D
authors: Michell
authors: Tianxiao
authors: T
authors: Huan
authors: Yahua
authors: Y
authors: Zhang
authors: Satoshi
authors: S
authors: Takaki
authors: Jens
authors: J
authors: Titze
authors: Daniel
authors: D
authors: Levy
authors: David G
authors: DG
authors: Harrison
authors: Meena S
authors: MS
authors: Madhur
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D006973:Hypertension / Q000235:genetics* / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009393:Nephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018384:Oxidative Stress; D013601:T-Lymphocytes / Q000276:immunology; D014657:Vasculitis / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D007371:Interferon-gamma