Evidence map›Paper›PMID 25776069›Full record

ArticleHypertension (Dallas, Tex. : 1979)2015

Mutation of SH2B3 (LNK), a genome-wide association study candidate for hypertension, attenuates Dahl salt-sensitive hypertension via inflammatory modulation.

Nathan P Rudemiller, Hayley Lund, Jessica R C Priestley, Bradley T Endres, Jeremy W Prokop, Howard J Jacob, Aron M Geurts, Eric P Cohen, David L Mattson

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Hypertension (Dallas, Tex. : 1979), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.

0numbers the graph read from it
0cells of the map it votes in
53citing papers in PubMed
3.9field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

53 citing papers in PubMed, 64 citations in OpenAlex.

  1. Lnk Governs chemokine-directed trafficking of CD8Molecular therapy. Oncology · 2026
    Article
  2. Review
  3. Review
  4. Article
  5. Immune and inflammatory mechanisms in hypertension.Nature reviews. Cardiology · 2024
    Review
  6. A new immune disease: systemic hypertension.Clinical kidney journal · 2023
    Review
  7. Review
  8. Article
  9. A Single Nucleotide Polymorphism inCirculation research · 2022
    Article
  10. Article
  11. Current Understanding of Pressure Natriuresis.Electrolyte & blood pressure : E & BP · 2021
    Review
  12. Review
  13. Article
  14. Review
  15. Review
  16. Article
  17. Emerging Role of the Inflammasome and Pyroptosis in Hypertension.International journal of molecular sciences · 2021
    Review
  18. Review
  19. Article
  20. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors at 1 institution in 1 country.

Nathan P RudemillerFrom the Department of Physiology (N.P.R., H.L., J.R.C.P., B.T.E., J.W.P., H.J.J., A.M.G., D.L.M.), and Human and Molecular Genetics Center (B.T.E., J.W.P., H.J.J., A.M.G.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Medical College of Wisconsin, Zablocki Veterans Affairs Medical Center, Milwaukee (E.P.C.). nrudemiller@mcw.edu.
Hayley LundFrom the Department of Physiology (N.P.R., H.L., J.R.C.P., B.T.E., J.W.P., H.J.J., A.M.G., D.L.M.), and Human and Molecular Genetics Center (B.T.E., J.W.P., H.J.J., A.M.G.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Medical College of Wisconsin, Zablocki Veterans Affairs Medical Center, Milwaukee (E.P.C.).
Jessica R C PriestleyFrom the Department of Physiology (N.P.R., H.L., J.R.C.P., B.T.E., J.W.P., H.J.J., A.M.G., D.L.M.), and Human and Molecular Genetics Center (B.T.E., J.W.P., H.J.J., A.M.G.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Medical College of Wisconsin, Zablocki Veterans Affairs Medical Center, Milwaukee (E.P.C.).
Bradley T EndresFrom the Department of Physiology (N.P.R., H.L., J.R.C.P., B.T.E., J.W.P., H.J.J., A.M.G., D.L.M.), and Human and Molecular Genetics Center (B.T.E., J.W.P., H.J.J., A.M.G.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Medical College of Wisconsin, Zablocki Veterans Affairs Medical Center, Milwaukee (E.P.C.).
Jeremy W ProkopFrom the Department of Physiology (N.P.R., H.L., J.R.C.P., B.T.E., J.W.P., H.J.J., A.M.G., D.L.M.), and Human and Molecular Genetics Center (B.T.E., J.W.P., H.J.J., A.M.G.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Medical College of Wisconsin, Zablocki Veterans Affairs Medical Center, Milwaukee (E.P.C.).
Howard J JacobFrom the Department of Physiology (N.P.R., H.L., J.R.C.P., B.T.E., J.W.P., H.J.J., A.M.G., D.L.M.), and Human and Molecular Genetics Center (B.T.E., J.W.P., H.J.J., A.M.G.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Medical College of Wisconsin, Zablocki Veterans Affairs Medical Center, Milwaukee (E.P.C.).
Aron M GeurtsFrom the Department of Physiology (N.P.R., H.L., J.R.C.P., B.T.E., J.W.P., H.J.J., A.M.G., D.L.M.), and Human and Molecular Genetics Center (B.T.E., J.W.P., H.J.J., A.M.G.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Medical College of Wisconsin, Zablocki Veterans Affairs Medical Center, Milwaukee (E.P.C.).
Eric P CohenFrom the Department of Physiology (N.P.R., H.L., J.R.C.P., B.T.E., J.W.P., H.J.J., A.M.G., D.L.M.), and Human and Molecular Genetics Center (B.T.E., J.W.P., H.J.J., A.M.G.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Medical College of Wisconsin, Zablocki Veterans Affairs Medical Center, Milwaukee (E.P.C.).
David L MattsonFrom the Department of Physiology (N.P.R., H.L., J.R.C.P., B.T.E., J.W.P., H.J.J., A.M.G., D.L.M.), and Human and Molecular Genetics Center (B.T.E., J.W.P., H.J.J., A.M.G.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Medical College of Wisconsin, Zablocki Veterans Affairs Medical Center, Milwaukee (E.P.C.).
Milwaukee VA Medical Center · US

Funding

Therapeutic Effects of mTOR Inhibition in Salt-Sensitive HypertensionP01HL116264 · NHLBI · MEDICAL COLLEGE OF WISCONSIN · PI COWLEY, ALLEN W · 2013 to 2021
$18.7M
Mechanistic characterization of genes for hypertension and renal disease.RC2HL101681 · NHLBI · MEDICAL COLLEGE OF WISCONSIN · PI JACOB, HOWARD J · 2009 to 2010
$6.6M
INTEGRATED PHYSIOLOGY TRAINING--MOLECULE TO ORGANISMT32HL007852 · NHLBI · MEDICAL COLLEGE OF WISCONSIN · PI Matthew Robert Hodges · 1996 to 2026
$6.5M
Role of CD247 in Salt-Sensitive Hypertension and Renal DiseaseR01DK096859 · NIDDK · MEDICAL COLLEGE OF WISCONSIN · PI MATTSON, DAVID L. · 2012 to 2016
$1.7M
NHLBI NIH HHS HL116264NHLBI NIH HHS P01 HL116264NHLBI NIH HHS RC2 HL101681NHLBI NIH HHS RC2-HL101681NHLBI NIH HHS T32 HL007852NIDDK NIH HHS DK-96859NIDDK NIH HHS R01 DK096859
6 · The paper itself

Abstract

Human genome-wide association studies have linked SH2B adaptor protein 3 (SH2B3, LNK) to hypertension and renal disease, although little experimental investigation has been performed to verify a role for SH2B3 in these pathologies. SH2B3, a member of the SH2B adaptor protein family, is an intracellular adaptor protein that functions as a negative regulator in many signaling pathways, including inflammatory signaling processes. To explore a mechanistic link between SH2B3 and hypertension, we targeted the SH2B3 gene for mutation on the Dahl salt-sensitive (SS) rat genetic background with zinc-finger nucleases. The resulting mutation was a 6-bp, in-frame deletion within a highly conserved region of the Src homology 2 (SH2) domain of SH2B3. This mutation significantly attenuated Dahl SS hypertension and renal disease. Also, infiltration of leukocytes into the kidneys, a key mediator of Dahl SS pathology, was significantly blunted in the Sh2b3(em1Mcwi) mutant rats. To determine whether this was because of differences in immune signaling, bone marrow transplant studies were performed in which Dahl SS and Sh2b3(em1Mcwi) mutants underwent total body irradiation and were then transplanted with Dahl SS or Sh2b3(em1Mcwi) mutant bone marrow. Rats that received Sh2b3(em1Mcwi) mutant bone marrow had a significant reduction in mean arterial pressure and kidney injury when placed on a high salt diet (4% NaCl). These data further support a role for the immune system as a modulator of disease severity in the pathogenesis of hypertension and provide insight into inflammatory mechanisms at play in human hypertension and renal disease.

Indexed as

MutationAdaptor Proteins, Signal TransducingAnimalsBlood PressureDNAElectrophoresis, Polyacrylamide GelGenome-Wide Association StudyHypertensionImmunity, CellularInflammationKidneyProteinsRatsRats, Inbred DahlRats, Mutant StrainsReal-Time Polymerase Chain ReactionAdaptor Proteins, Signal TransducingDNAProteinsSh2b3 protein, rathypertensionimmune systemkidneylymphocytesrats

Identifiers

PMID25776069
PMCPMC4412596
OpenAlexW2153514651

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.