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PMID: 22189943 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Interaction between uric acid and HMGB1 translocation and release from endothelial cells.

American journal of physiology. Renal physiology ·Vol. 302 ·No. 6 ·2012-03-15 ·Pages F730-41

Rabadi MM, Kuo MC, Ghaly T, Rabadi SM, Weber M, Goligorsky MS, Ratliff BB

Abstract

We aimed to investigate the potential relationship between alarmins [acting via Toll-like receptor-4 (TLR4)], uric acid (UA), and high-mobility group box-1 protein (HMGB1) during acute kidney injury. UA, which is significantly increased in the circulation following renal ischemia-reperfusion injury (IRI), was used both in vitro and in vivo as an early response-signaling molecule to determine its ability to induce the secretion of HMGB1 from endothelial cells. Treatment of human umbilical vein endothelial cells (HUVEC) with UA resulted in increased HMGB1 mRNA expression, acetylation of nuclear HMGB1, and its subsequent nuclear-cytoplasmic translocation and release into the circulation, as determined by Western blotting and immunofluorescence. Treatment of HUVEC with UA and a calcium mobilization inhibitor (TMB-8) or a MEK/Erk pathway inhibitor (U0126) prevented translocation of HMGB1 from the nucleus, resulting in reduced cytoplasmic and circulating levels of HMGB1. Once released, HMGB1 in autocrine fashion promoted further HMGB1 release while also stimulating NF-κB activity and increased angiopoietin-2 expression and protein release. Transfection of HUVEC with TLR4 small interfering (si) RNA reduced HMGB1 levels during UA and HMGB1 treatment. In summary, UA after IRI mediates the acetylation and release of HMGB1 from endothelial cells by mechanisms that involve calcium mobilization, the MEK/Erk pathway, and activation of TLR4. Once released, HMGB1 promotes its own further cellular release while acting as an autocrine and paracrine to activate both proinflammatory and proreparative mediators.

MeSH Terms
Animals Calcium/metabolism Endothelial Cells/metabolism Extracellular Signal-Regulated MAP Kinases/genetics,metabolism Gene Expression Regulation/drug effects HMGB1 Protein/genetics,metabolism Humans MAP Kinase Kinase Kinases/genetics,metabolism MAP Kinase Signaling System/physiology Male Mice Protein Transport RNA Interference RNA, Small Interfering Toll-Like Receptor 4/genetics,metabolism Uric Acid/pharmacology
Chemicals
HMGB1 Protein RNA, Small Interfering TLR4 protein, human Toll-Like Receptor 4 Uric Acid Extracellular Signal-Regulated MAP Kinases MAP Kinase Kinase Kinases Calcium
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Rabadi May M
Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Kuo Mei-Chuan
Ghaly Tammer
Rabadi Seham M
Weber Mia
Goligorsky Michael S
Ratliff Brian B
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Article Info
Journal
American journal of physiology. Renal physiology
Abbr.
Am J Physiol Renal Physiol
ISSN
1522-1466
DOI
10.1152/ajprenal.00520.2011
Published
2012-03-15
Epub
2011-00-21
Pages
F730-41
Language
English
Region
United States
NLM ID
100901990
PMCID
PMC3311321
Subset
IM
Grants
NIDDK NIH HHS · R01 DK084394 · United States
NIDDK NIH HHS · DK54602 · United States
NIDDK NIH HHS · DK052783 · United States
NIDDK NIH HHS · DK45462 · United States
External Links
PubMed source DOI: 10.1152/ajprenal.00520.2011 PMC Full Text View journal details
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