Journal
KIDNEY INTERNATIONAL
Volume 87, Issue 1, Pages 95-108Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2014.217
Keywords
acute renal failure; endothelial cells; ischemia-reperfusion; renal physiology
Categories
Funding
- NIH [DK54602, DK052783, DK45462]
- AHA [12SDG9080006]
- Westchester Artificial Kidney Foundation
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK052783, R01DK045462, R01DK054602] Funding Source: NIH RePORTER
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High-mobility group box 1 (HMGB1) undergoes acetylation, nuclear-to-cytoplasmic translocation, and release from stressed kidneys, unleashing a signaling cascade of events leading to systemic inflammation. Here, we tested whether the deacetylase activity of Sirtuin1 (SIRT1) participates in regulating nuclear retention of HMGB1 to ultimately modulate damage signaling initiated by HMGB1 secretion during stress. When immunoprecipitated acetylated HMGB1 was incubated with SIRT1, HMGB1 acetylation decreased by 57%. Proteomic analysis showed that SIRT1 deacetylates HMGB1 at four lysine residues (55, 88, 90, and 177) within the proinflammatory and nuclear localization signal domains of HMGB1. Genetic ablation or pharmacological inhibition of SIRT1 in endothelial cells increased HMGB1 acetylation and translocation. In vivo, deletion of SIRT1 reduced nuclear HMGB1 while increasing its acetylation and release into circulation during basal and ischemic conditions, causing increased renal damage. Conversely, resveratrol pretreatment led to decreased HMGB1 acetylation, its nuclear retention, decreased systemic release, and reduced tubular damage. Thus, a vicious cycle is set into motion in which the inflammation-induced repression of SIRT1 disables deacetylation of HMGB1, facilitates its nuclear-to-cytoplasmic translocation, and systemic release, thereby maintaining inflammation.
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