HMGB1 in renal ischemic injury

Abstract

<jats:p>Factors that initiate cellular damage and trigger the inflammatory response cascade and renal injury are not completely understood after renal ischemia-reperfusion injury (IRI). High-mobility group box-1 protein (HMGB1) is a damage-associated molecular pattern molecule that binds to chromatin, but upon signaling undergoes nuclear-cytoplasmic translocation and release from cells. Immunohistochemical and Western blot analysis identified HMGB1 nuclear-cytoplasmic translocation and release from renal cells (particularly vascular and tubular cells) into the venous circulation after IRI. Time course analysis indicated HMGB1 release into the venous circulation progressively increased parallel to increased renal ischemic duration. Ethyl pyruvate (EP) treatment blocked H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>(oxidative stress)-induced HMGB1 release from human umbilical vein endothelial cells in vitro, and in vivo resulted in nuclear retention and significant blunting of HMGB1 release into the circulation after IRI. EP treatment before IRI improved short-term serum creatinine and albuminuria, proinflammatory cyto-/chemokine release, and long-term albuminuria and fibrosis. The renoprotective effect of EP was abolished when exogenous HMGB1 was injected, suggesting EP's therapeutic efficacy is mediated by blocking HMGB1 translocation and release. To determine the independent effects of circulating HMGB1 after injury, exogenous HMGB1 was administered to healthy animals at pathophysiological dose. HMGB1 administration induced a rapid surge in systemic circulating cyto-/chemokines (including TNF-α, eotaxin, G-CSF, IFN-γ, IL-10, IL-1α, IL-6, IP-10, and KC) and led to mobilization of bone marrow CD34+Flk1+ cells into the circulation. Our results indicate that increased ischemic duration causes progressively enhanced HMGB1 release into the circulation triggering damage/repair signaling, an effect inhibited by EP because of its ability to block HMGB1 nuclear-cytoplasmic translocation.</jats:p>

Remote ischaemic preconditioning in orthotopic liver transplantation (RIPCOLT trial): a pilot randomized controlled feasibility study

“…TNFα, is a key cytokine shown to be upregulated early following IR injury and to promote recruitment of lymphocytes to the ischaemic injury 41 . Other cytokines that have been implicated in IR injury in small animal models include IL-2 42 , IL-6 43 , IL8 44 , IL-17 45 and IFNγ 43 and these were measured in this study. A previous observational study in humans undergoing liver transplantation 46 measured circulating serum cytokine levels at 24 hours post transplantation and found that the in the majority of patients, circulating levels were below the detectable level especially IFNγ (99%) and TNFα (77%).…”

Messengers without Borders

“…Yet, the existing dichotomy of HMGB1 effects shows that its proinflammatory potency prevails over its proregenerative properties: inhibition of HMGB1 secretion by pretreatment with ethyl pyruvate ameliorates both the AKI and, in contrast to the inhibition of exocytosis of Weibel-Palade bodies, the long-term fibrotic changes seen in the postischemic kidneys. 1,2 Experimental findings and analysis of literature presented above should evoke the realization that AKI is a paradigm of a localized damage triggering systemic inflammatory disease (Figure 3). Whereas the local inflammatory process, when unperturbed, has a tendency to resolve itself, the systemic inflammatory response, when sufficiently intense and/ or prolonged, may not only exacerbate the local disease, but can also involve other organs (heart, lungs, and liver), accounting for the increased mortality even in cases of a mild AKI.…”

Beyond Tissue Injury—Damage-Associated Molecular Patterns, Toll-Like Receptors, and Inflammasomes Also Drive Regeneration and Fibrosis

“…89,100,[142][143][144][145][146] In addition, lethality in sepsis relates to the release of HMGB1, histones, decorin, or biglycan. 42,78,100,144 This process seems to preferentially involve DAMP-mediated endothelial dysfunction via TLR2/TLR4, which increases vascular permeability, shock, and hypoperfusion.…”