BRIEF REVIEW
www.jasn.org
Messengers without Borders: Mediators of Systemic Inflammatory Response in AKI Brian B. Ratliff, May M. Rabadi, Radovan Vasko, Kaoru Yasuda, and Michael S. Goligorsky Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York
ABSTRACT The list of signals sent by an injured organ to systemic circulation, so-called danger signals, is growing to include multiple metabolites and secreted moieties, thus revealing a highly complex and integrated network of interlinked systemic proinflammatory and proregenerative messages. Emerging new data indicate that, apart from the well established local inflammatory response to AKI, danger signaling unleashes a cascade of precisely timed, interdependent, and intensity-gradated mediators responsible for development of the systemic inflammatory response. This fledgling realization of the importance of the systemic inflammatory response to the localized injury and inflammation is at the core of this brief overview. It has a potential to explain the additive effects of concomitant diseases or preexisting chronic conditions that can prime the systemic inflammatory response and exacerbate it out of proportion to the actual degree of acute kidney damage. Although therapies for ameliorating AKI per se remain limited, a potentially powerful strategy that could reap significant benefits in the future is to modulate the intensity of danger signals and consequently the systemic inflammatory response, while preserving its intrinsic proregenerative stimuli. J Am Soc Nephrol 24: 529–536, 2013. doi: 10.1681/ASN.2012060633
AKI, despite 7 decades of thorough investigations, still holds pathogenetic secrets and limited therapeutic success stories, not for the want of innumerable trials. Although the intensity of a noxious stimulus leads to a proportional degree of kidney injury,1,2 these linear relations disappear when the stressor and renal injury are contrasted against the response of the whole organism. For instance, several epidemiologic studies have demonstrated that even very mild AKI, not requiring any therapeutic and/or dialytic intervention, associates with a significantly increased mortality compared with those patients who have not developed AKI, despite the same inciting pathologic condition.3–5 Furthermore, it has been known for a long time that mortality in AKI J Am Soc Nephrol 24: 529–536, 2013
patients in intensive care units is better predicted by the concomitant dysfunction of other organ systems: multivariate logistic regression modeling shows that mortality increases from 12% to 100% when AKI patients have one to five failing organ systems, respectively.6 The adjusted odds ratio of death is increased several-fold for cardiovascular, hepatic, respiratory, and neurologic failure, and massive transfusion and age .60 years. On the basis of epidemiologic findings in 3591 consecutive intensive care unit patients, Kelly examined effects of acute renal ischemia on heart function7 and described elevated systemic levels of TNF-a and IL-1, together with increased myeloperoxidase activity and upregulation of intercellular adhesion molecule 1 (ICAM-1) mRNA
in the heart, accompanied by increased numbers of apoptotic cardiomyocytes, increased left ventricular end-diastolic and end-systolic diameter, and decreased functional shortening on echocardiograms. Notably, all of these changes occurred at a time when animals were not severely uremic and these phenomena could not be replicated by bilateral nephrectomy, suggesting that ischemic insult per se was responsible for observed distant effects. Follow-up studies demonstrated that similar distant effects are found in lungs, brain, and other organs.8 This set of observations resonates with the similar findings in patients with CKD exhibiting a dramatic increase in mortality at the time when their renal function is only moderately declined. Importantly, it also provides a strong argument in favor of a broader interpretation of AKI as a disease with systemic manifestations. The following brief overview offers a revision of AKI based on the fledgling realization that this local syndrome in reality evokes
Published online ahead of print. Publication date available at www.jasn.org. Present addresses: Dr. Radovan Vasko, Department of Nephrology, Goettingen University, Germany; Dr. Kaoru Yasuda, the Department of Nephrology, Nagoya University, Japan. Correspondence: Dr. Michael S. Goligorsky or Dr. Brian B. Ratliff, Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, 15 Dana Road, BSB C-06, Valhalla, NY 10595. Email: michael_goligorsky@nymc. edu or
[email protected] Copyright © 2013 by the American Society of Nephrology
ISSN : 1046-6673/2404-529
529
BRIEF REVIEW
www.jasn.org
a systemic inflammatory response, which has much more profound organismal consequences than the local destructive and inflammatory processes.
LOCAL INFLAMMATION
Much has been reported about the local inflammatory processes in the acutely injured kidney. Activation of vascular endothelial cells and the chemoattractive guidance cues emanating from injured tubular epithelial cells, facilitate transmigration of PMN, monocytes/macrophages, and lymphocytes. The process is driven by increased expression of adhesion molecules like ICAM-1, vascular cell adhesion molecule 1, selectins, leukocyte-endothelial integrins, and fractalkine receptor CX3CR1 and its ligand.9 Most investigators find that preventing infiltration by inflammatory cells through either depleting PMN, macrophages, and T lymphocytes or blocking leukocyte-endothelial interactions results in renoprotection.9–12 These invading cells degranulate with release of proteolytic products, elaborate cytokines and chemokines, and reactive oxygen and nitrogen species, all of which participate in a well orchestrated acute aseptic inflammation of the kidneys. Two subsets of monocytes, inflammatory Gr1+ and patrolling Gr1lo cells, when they infiltrate the kidney give rise to dendritic cells.13 These cells coexpress F4/80 molecule, fractalkine receptor CX3CR1, CD11c, and MHC class II. Kidney dendritic cells create an extensive network throughout the interstitium surveying the renal parenchymal microenvironment for tubular, glomerular, or filtered autoantigens. Hypoxia, endotoxins, and multiple drugs activate these professional antigenpresenting cells. Kidney dendritic cells provide the line of defensive response to ischemia by secreting TNF-a, the function taken by vascular endothelial cells later in the process,14 and ablation of the source of dendritic cells with clodronate-containing iposomes exerts renoprotective effects against ischemia. In contrast, depleting kidney dendritic cells was found to aggravate renal injury in cisplatin-induced nephrotoxicity.15 530
BLACK BOX ANALYSIS OF POSTISCHEMIC KIDNEYS
The danger model, a conceptual link between immune and nonimmune-mediated tissue injury, was proposed by Matzinger and has since received considerable experimental support.16 The essence of this theory is that many signaling elements initiating inflammation in response to invading organisms and alarm signals released from injured/necrotic tissues are shared and elicit similar responses at the tissue and organismal levels. A host of alarm signals, so-called alarmins, has been described in immunologic literature; remarkably, these include not only bacterial products, but also an array of cellular metabolites and extracellular matrix proteins.17 Despite all of the progress made during the past few years in the expanding field of alarmins, the precise unbiased analysis of the output from an ischemic organ, as complex as the kidney, has not been performed. Ischemia is not only a trigger for proinflammatory signaling, it is also one of the potent signals to mobilize stem cells; this has been unequivocally documented in humans and in experimental animals with myocardial ischemia, ischemic stroke, and renal ischemia.18–22 Both uric acid, a prototypical fast-acting alarm signal, and highmobility group box 1 protein (HMGB1) have also been recently involved in the mobilization and homing of endothelial progenitor cells (EPCs) to ischemic tissues.22–25 Considering the importance of the analysis of kidney output in assigning to individual metabolites a role in orchestrating selective functional responses in the danger model, the need for such a screening should become ever more obvious. For the purposes of such an analysis of alarm signals, it is essential to study the flow of output signals generated by an organ in response to changes in the input signals. Using input and output signals to gain insights into the operation of a system has long been exploited in electronics and cybernetics and referred to as a black box analysis. We applied the black box principles to the study of metabolic signals produced by the kidney
Journal of the American Society of Nephrology
or systemically in response to the imposed ischemic insult. To obtain as broad detection as possible, several platforms were utilized for analyses; these included a multiplex analysis of cytokines and chemokines, targeted analysis of individual metabolites, and metabolomic analysis of arterial and renal venous blood. Some examples of venous-arterial gradients are presented in Figures 1 and 2, which illustrate that the ischemic kidney is the source of endothelin-1, HMGB1, and multiple cytokines and chemokines released into the circulation, whereas a different set of mediators is produced systemically in response to locally secreted products.
SYSTEMIC INFLAMMATION: THREE WAVES OF DANGER SIGNALING
The pathophysiology of renal ischemiareperfusion injury (IRI) includes direct cellular damage caused by ischemia or nephrotoxins, as well as delayed renal injury resulting from systemic inflammatory response. Although the underlying mechanisms for acute renal injury have been studied extensively, factors that lead to the propagation of the local inflammatory responses and subsequent aggravation of renal injury remain poorly investigated. Purine metabolism represents the first line of defense against noxious stimuli. Uric acid has emerged as a crucial, very early mediator of damage response to injury, particularly after renal ischemic insult. Uric acid is currently recognized as a prototypical alarm signal, which undergoes a surge in the plasma shortly after renal ischemia-reperfusion—this provides the first wave of danger signaling. 22,23 Xanthine oxidoreductase, a member of molybdoenzyme family, catalyzes the oxidation of hypoxanthine to xanthine and finally to uric acid. It exists in two interconvertible forms: xanthine oxidase (uses O2 to generate superoxide) and xanthine dehydrogenase, intracellularly the predominant form (preferentially reduces NAD+ and thus does not produce oxygen free radicals). Upregulation of xanthine oxidase activity has J Am Soc Nephrol 24: 529–536, 2013
www.jasn.org
Figure 1. Endothelin-1 and HMGB1 in the arterial and venous blood of postischemic kidneys. Endothelin-1 (A) and HMGB1 (B and C) are measured in the renal venous blood after bilateral ischemia-reperfusion (30 minutes of ischemia induced by renal arterial clamping in 12-week-old male C57 mice) and in systemic arterial blood collected from the left ventricle. (A) Endothelin-1 is measured by ELISA assay (Caymen Chemicals). HMGB1 is analyzed by Western blot (B) and normalized to total protein content (C). Levels of endothelin-1 and HMGB1 are increased in the venous blood within minutes and 1 hour after ischemiareperfusion, indicating that both endothelin-1 and HMGB1 are rapidly released by the kidneys after ischemic insult. Differences in venous-arterial content of endothelin-1 and HMGB1 are illustrated by line graph overlays in the figures. *P,0.05 versus control (same group); #P,0.05 versus 24 hours (same group); +P,0.05 versus arterial. n=6. Note that the scale of venous-arterial difference does not correspond to the y-axis scale.
been demonstrated in various ischemic diseases.26 Uric acid release after IRI unleashes a cascade of secondary events. The relatively fast damage response is accomplished by exocytosis of Weibel-Palade bodies that is J Am Soc Nephrol 24: 529–536, 2013
mediated by Toll-like receptors (TLRs) 2 and 4.23 Exocytosis of Weibel-Palade bodies represents the second wave of response to noxious stimuli. These endotheliaspecific organelles contain vWf, IL-8, angiopoietin-2, eotaxin, endothelin-1,
BRIEF REVIEW
and big endothelin-1 together with endothelin-converting enzyme, among other biologically active molecules. Exocytosis of Weibel-Palade bodies releases these normally sequestered substances to the bloodstream. Kuo et al.23 documented release of angiopoietin-2, eotoxin, and IL-8 to the systemic circulation. We recently demonstrated a postischemic venousto-arterial gradient of endothelin-1 (Figure 1A). In general, exocytosis of Weibel-Palade bodies results in the release of components that possess either proinflammatory or proregenerative properties. The biologic role of the former predominates in the acute phase of an injury, whereas the role of the latter appears to predominate in the long-term outcome: inhibition of exocytosis of Weibel-Palade bodies, while ameliorating acute renal dysfunction after the insult, tends to exaggerate the chronic fibrotic consequences.27 Considering the plethora of biologically active constituents of Weibel-Palade bodies, it is possible that they can exert mutually opposing actions. It would be a future goal to analyze each of them separately and to replenish those that are necessary for regeneration, while suppressing those that exacerbate inflammation. We reasoned that the surge in uric acid after acute renal injury also leads to exocytosis of other internal storage pools and secretory lysosomes, the known vehicles for the release of HMGB1. Previous findings28–30 support the idea that HMGB1 is released from endothelial cells. HMGB1 is translocated from the nucleus to the cytoplasm and released from the cell upon stimulation by LPS or TNF-a. 28 However, the release of HMGB1 from endothelial cells activated by either LPS or TNF-a is relatively slow. In contrast, in vivo intrarenal injection of uric acid, mimicking its postischemic surge, or renal ischemia-reperfusion insult lead to HMGB1 nucleocytoplasmic translocation and subsequent release from the cytosol into the circulation within 1 hour. This finding is further supported by our in vitro studies in cultured endothelial cells demonstrating a similar time-course of HMGB1 release after application of uric acid.25
Systemic Inflammatory Response to Renal Insult
531
BRIEF REVIEW
www.jasn.org
Figure 2. Levels of cytokines/chemokines in the arterial and renal venous blood of postischemic kidneys. Using Luminex Technology, cytokines/chemokines are measured in the renal venous blood after bilateral ischemia-reperfusion (30 minutes of ischemia induced by renal arterial clamping in 12-week-old male C57 mice) and in systemic arterial blood collected from the left ventricle. IFN-g, IL-1a, and MMP-9 increase in the venous blood exiting the kidney after ischemia-reperfusion, with no significant change in the systemic arterial blood. MIP-1a,
532
Journal of the American Society of Nephrology
J Am Soc Nephrol 24: 529–536, 2013
www.jasn.org
HMGB1, discovered .30 years ago as a DNA binding protein,29 also functions as a transcription factor and secures the maintenance of genome stability.30,31 This chromatin-binding nuclear protein and damage-associated molecular pattern molecule is an example of multifaceted biologic activities with switches from one to another as determined by its translocation between compartments. In the nucleus, this ubiquitous 215 amino acid protein of 30 kD serves as a DNA chaperone participating in DNA replication, transcription, and repair and enhances the activity of several transcription factors.32 It has two DNA binding domains, the high-mobility group A-box and Bbox domains. 33–36 The main nuclear function of HMGB1 is to bend DNA to allow proper physical interactions between different transcription factors and the chromatin.37 The acetylation of active DNA binding sites of HMGB1 decreases its affinity for DNA, allowing for its escape from the nucleus.37 The nuclear export of HMGB1 engages the nuclear exporter protein, chromosome region maintenance 1,38 although other mechanisms may also be involved in HMGB1 release from the nuclei. For instance, Youn et al. have shown in monocytes that phosphorylation of HMGB1 modulates its nucleocytoplasmic shuttling.39–41 When HMGB1 is phosphorylated, its binding to the nuclear cargo carrier protein, karyopherin-a1, is reduced and HMGB1 is translocated to the cytoplasm and eventually secreted into the extracellular compartment.42 Translocation of HMGB1 from the nucleus to the cytoplasm also involves its acetylation, 38,39,41 an effect possibly mediated by decreased deacetylase activity.43 Furthermore, in the absence of calcium, HMGB1 DNA binding properties are enhanced. 44 – 4 6 Recent studies suggest the possible role of elevated cytosolic calcium concentration and
calcium/calmodulin-dependent and mitogen-activated protein kinase kinase (MEK)/extracellular signal–regulated kinase (ERK)–dependent regulatory pathways in the nucleocytoplasmic shuttling and release of HMGB1.39,40 Oh et al. showed in monocytes that HMGB1 secretion is induced by a calcium ionophore and inhibited by calcium chelators.39 These authors found that calcium-dependent protein kinase C phosphorylates HMGB1 in LPS-activated cells.39 The importance of calcium in HMGB1 secretion from monocytes was further emphasized by Gardella et al,47 who showed after HMGB1 translocation from the nucleus to the cytoplasm that it is accumulated in the secretory lysosomes and elevated cytosolic calcium regulates the exocytosis of these secretory organelles.47 We examined the potential mechanism by which uric acid may cause release and secretion of HMGB1 from endothelial cells. Our findings indicate that release of calcium from intercellular inositol-trisphosphate-sensitive stores is crucial for the uric acid-mediated release of HMGB1 from the cell. Data also showed that inhibition of the MEK/ERK pathway prevents uric acid-induced nucleocytoplasmic shuttling and release, thus indicating that the mechanism of uric acid-induced secretion of HMGB1 involves both intracellular calcium mobilization and the MEK/ERK pathway.25 Once released into the circulation, HMGB1 exerts potent cytokine-like proinflammatory effects.48 HMGB1 has been shown to interact with the receptor for advanced glycation end-products, TLR2 and TLR4, triggering receptor expressed on myeloid cells 1, and CD24 on target cells and leads to activation of NF-kB–mediated pathways. 49 –5 5 HMGB1 is released passively from necrotic cells and actively by various stressed cells, such as monocytes, macrophages, and T cells, all of which play a role in the inflammatory response to
BRIEF REVIEW
injury.41 The proinflammatory effects of HMGB1 have been recently targeted to determine the beneficial effects of blocking HMGB1 release in the circulation. In studies of endotoxemia, neutralizing antibodies against HMGB1 prevented lethality.56,57 In a model of IRI, neutralizing antibodies against HMGB1 offered significant protection against renal injury, as was concluded based on the reduction in tubular cell apoptosis, blunted elevation of serum creatinine, BUN, TNF-a expression, and pathologic manifestations of injury. 58 However, it should be kept in mind that HMGB1 is also involved in regenerative processes, as judged from the observations that HMGB1 induces both migration and proliferation of vascular-associated stem cells.24,59 Release of HMGB1 has been reported after IRI.58,60–62 Data from Lu et al.63 and our findings 25 demonstrate that the ischemic kidney is the originator of surging HMGB1 in the circulation, that endothelial cells contribute to it, and that uric acid signaling can mimic this process both in vitro and in vivo. We showed that after ischemic insult, HMGB1 is released into the renal circulation within 1–3 hours (Figure 1, B and C).25 Moreover, the surge in HMGB1 is capable of increasing several pro- and antiinflammatory cytokines in the circulation and is in part responsible for AKI, as judged by the fact that preventing nucleocytoplasmic translocation of HMGB1 ameliorates renal dysfunction. This is explained by the fact that once released into the circulation, HMGB1 acts as a damage-associated molecular pattern molecule. HMGB1 acts on macrophages to release TNF-a and IL-6,57 and stimulates the release of TNF-a, IL-1a, IL-1b, IL-6, IL-8, and macrophage inflammatory protein 1a (MIP-1a), but not MIP-1b, from monocytes.64 HMGB1 induces the release of TNF-a, IL-8, granulocyte colonystimulating factor, and expression of
IL-1b, KC, VEGF, and granulocyte macrophage colony-stimulating factor increase in the systemic circulation with minimal change in the renal venous blood. These results indicate that cytokines/chemokine release from the kidney differs from peripheral release during IRI. *P,0.05 versus control (same group); #P,0.05 versus 24 hours (same group); ‡P,0.05 versus 1 minute and 24 hours; +P,0.05 versus arterial. n=6. MMP-9, matrix metalloproteinase-9; KC, kinase C; VEGF, vascular endothelial growth factor. J Am Soc Nephrol 24: 529–536, 2013
Systemic Inflammatory Response to Renal Insult
533
BRIEF REVIEW
www.jasn.org
adhesion molecules such as ICAM-1 and E-selectin in endothelial cells.56,65–67 One hour after infusion of exogenous HMGB1, levels of IL-6, IFN-g–induced protein 10, and MIP-1a surge in the plasma, followed, after 3 hours, by the increase in eotaxin and granulocyte colonystimulating factor plasma concentration, while IL-8 and IL-10 remain elevated during this time interval (Figure 2). Recent reports also identify HMGB1 as a strong chemoattractant and a stimulator of proliferation for vessel-associated stem cells (endothelial progenitor cells and mesoangioblasts)24,59 as well as a mobilizing agonist for bone marrow stem cells, thus underscoring its potential proregenerative properties.68 It is involved in the healing of injured tissues, such as myocardium and skin wounds.69–72 In addition, HMGB1 is reported to possess proangiogenic activity.73–76 Its ability to promote proliferation, migration, and differentiation of several cell types, particularly those involved in angiogenesis, prompted us to examine the ability of HMGB1 to mobilize EPCs from the bone marrow. We observed significant mobilization of bone marrow EPCs and their initial sequestration in the spleen. These findings are consistent with the idea that HMGB1 mobilizes stem cells to promote angiogenesis and tissue repair after injury. 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 534
Figure 3. Consecutive waves of danger signaling after renal ischemic episode (see text for details). ET, endothelin. G-CSF, granulocyte colony-stimulating factor; WPB, WeibelPalade bodies; RAGE, receptor for advanced glycation end products.
even in cases of a mild AKI. Systemic inflammatory response is triggered by at least three waves of danger signaling, which regulate its intensity and timing (Figure 3). Systemic inflammatory response is intrinsically Janus-like, with the one face of it representing destructive inflammatory sequelae, while the other face is turned toward regeneration of damaged tissues. Induction of systemic inflammatory response as a companion of acute local injury explains the old dictum that patients die not from AKI, but with AKI. This fledgling realization of the importance of the systemic inflammatory response to the localized injury and inflammation has a potential to explain the added severity of concomitant diseases or preexisting chronic conditions that can prime the systemic inflammatory response and exacerbate it out of proportion to the actual acute kidney damage. And finally, although therapies for ameliorating AKI per se are limited, an additional potentially powerful strategy that could reap significant benefits in the future is to modulate the intensity of danger signals and consequently the systemic
Journal of the American Society of Nephrology
inflammatory response, while not perturbing its intrinsic proregenerative stimuli. ACKNOWLEDGMENTS Studies from the authors’ laboratories were supported in part by grants from the American Heart Association (12SDG9080006 to B.B.R.), the National Institutes of Health (DK54602, DK052783, DK45462), and the Westchester Artificial Kidney Foundation (to M.S.G.).
DISCLOSURES None.
REFERENCES 1. Chawla LS, Amdur RL, Amodeo S, Kimmel PL, Palant CE: The severity of acute kidney injury predicts progression to chronic kidney disease. Kidney Int 79: 1361–1369, 2011 2. Rabadi MM, Ghaly T, Goligorksy MS, Ratliff BB: HMGB1 in renal ischemic injury. Am J Physiol Renal Physiol 303: F873–F885, 2012 3. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW: Acute kidney injury, mortality,
J Am Soc Nephrol 24: 529–536, 2013
www.jasn.org
4.
5.
6.
7.
8.
9.
10. 11.
12.
13.
14.
15.
16. 17.
18.
19.
length of stay, and costs in hospitalized patients. J Am Soc Nephrol 16: 3365–3370, 2005 Coca SG, Peixoto AJ, Garg AX, Krumholz HM, Parikh CR: The prognostic importance of a small acute decrement in kidney function in hospitalized patients: A systematic review and meta-analysis. Am J Kidney Dis 50: 712– 720, 2007 Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, Hiesmayr M: Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: A prospective cohort study. J Am Soc Nephrol 15: 1597–1605, 2004 Schwilk B, Wiedeck H, Stein B, Reinelt H, Treiber H, Bothner U: Epidemiology of acute renal failure and outcome of haemodiafiltration in intensive care. Intensive Care Med 23: 1204–1211, 1997 Kelly KJ: Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol 14: 1549–1558, 2003 Li X, Hassoun HT, Santora R, Rabb H: Organ crosstalk: The role of the kidney. Curr Opin Crit Care 15: 481–487, 2009 Kinsey GR, Li L, Okusa MD: Inflammation in acute kidney injury. Nephron, Exp Nephrol 109: e102–e107, 2008 Chung AC, Lan HY: Chemokines in renal injury. J Am Soc Nephrol 22: 802–809, 2011 Ikeda M, Prachasilchai W, Burne-Taney MJ, Rabb H, Yokota-Ikeda N: Ischemic acute tubular necrosis models and drug discovery: A focus on cellular inflammation. Drug Discov Today 11: 364–370, 2006 Thurman JM: Triggers of inflammation after renal ischemia/reperfusion. Clin Immunol 123: 7–13, 2007 Hochheiser K, Tittel A, Kurts C: Kidney dendritic cells in acute and chronic renal disease. Int J Exp Pathol 92: 193–201, 2011 Dong X, Swaminathan S, Bachman LA, Croatt AJ, Nath KA, Griffin MD: Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury. Kidney Int 71: 619–628, 2007 Tadagavadi RK, Reeves WB: Renal dendritic cells ameliorate nephrotoxic acute kidney injury. J Am Soc Nephrol 21: 53–63, 2010 Matzinger P: The danger model: A renewed sense of self. Science 296: 301–305, 2002 Bianchi ME: DAMPs, PAMPs and alarmins: All we need to know about danger. J Leukoc Biol 81: 1–5, 2007 Adams V, Lenk K, Linke A, Lenz D, Erbs S, Sandri M, Tarnok A, Gielen S, Emmrich F, Schuler G, Hambrecht R: Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exerciseinduced ischemia. Arterioscler Thromb Vasc Biol 24: 684–690, 2004 Taguchi A, Soma T, Tanaka H, Kanda T, Nishimura H, Yoshikawa H, Tsukamoto Y, Iso H, Fujimori Y, Stern DM, Naritomi H, Matsuyama T: Administration of CD34+ cells after stroke enhances neurogenesis via
J Am Soc Nephrol 24: 529–536, 2013
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
angiogenesis in a mouse model. J Clin Invest 114: 330–338, 2004 Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T: Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5: 434–438, 1999 Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, Sasaki K, Shimada T, Oike Y, Imaizumi T: Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 103: 2776– 2779, 2001 Patschan D, Patschan S, Gobe GG, Chintala S, Goligorsky MS: Uric acid heralds ischemic tissue injury to mobilize endothelial progenitor cells. J Am Soc Nephrol 18: 1516– 1524, 2007 Kuo MC, Patschan D, Patschan S, CohenGould L, Park HC, Ni J, Addabbo F, Goligorsky MS: Ischemia-induced exocytosis of Weibel-Palade bodies mobilizes stem cells. J Am Soc Nephrol 19: 2321–2330, 2008 Chavakis E, Hain A, Vinci M, Carmona G, Bianchi ME, Vajkoczy P, Zeiher AM, Chavakis T, Dimmeler S: High-mobility group box 1 activates integrin-dependent homing of endothelial progenitor cells. Circ Res 100: 204– 212, 2007 Rabadi MM, Kuo MC, Ghaly T, Rabadi SM, Weber M, Goligorsky MS, Ratliff BB: Interaction between uric acid and HMGB1 translocation and release from endothelial cells. Am J Physiol Renal Physiol 302: F730– F741, 2012 Meneshian A, Bulkley GB: The physiology of endothelial xanthine oxidase: From urate catabolism to reperfusion injury to inflammatory signal transduction. Microcirculation 9: 161–175, 2002 Yasuda K, Vasko R, Hayek P, Ratliff B, Bicer H, Mares J, Maruyama S, Bertuglia S, Mascagni P, Goligorsky MS: Functional consequences of inhibiting exocytosis of Weibel-Palade bodies in acute renal ischemia. Am J Physiol Renal Physiol 302: F713–F721, 2012 Mullins GE, Sunden-Cullberg J, Johansson AS, Rouhiainen A, Erlandsson-Harris H, Yang H, Tracey KJ, Rauvala H, Palmblad J, Andersson J, Treutiger CJ: Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1. Scand J Immunol 60: 566–573, 2004 Goodwin GH, Sanders C, Johns EW: A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem 38: 14–19, 1973 Bianchi ME, Beltrame M: Upwardly mobile proteins. Workshop: The role of HMG proteins in chromatin structure, gene expression and neoplasia. EMBO Rep 1: 109–114, 2000 Bianchi ME, Beltrame M, Paonessa G: Specific recognition of cruciform DNA by nuclear
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
BRIEF REVIEW
protein HMG1. Science 243: 1056–1059, 1989 Tang D, Kang R, Zeh HJ 3rd, Lotze MT: Highmobility group box 1, oxidative stress, and disease. Antioxid Redox Signal 14: 1315– 1335, 2011 Ferrari S, Finelli P, Rocchi M, Bianchi ME: The active gene that encodes human high mobility group 1 protein (HMG1) contains introns and maps to chromosome 13. Genomics 35: 367–371, 1996 Rauvala H, Merenmies J, Pihlaskari R, Korkolainen M, Huhtala ML, Panula P: The adhesive and neurite-promoting molecule p30: Analysis of the amino-terminal sequence and production of antipeptide antibodies that detect p30 at the surface of neuroblastoma cells and of brain neurons. J Cell Biol 107: 2293–2305, 1988 Wen L, Huang JK, Johnson BH, Reeck GR: A human placental cDNA clone that encodes nonhistone chromosomal protein HMG-1. Nucleic Acids Res 17: 1197–1214, 1989 Paonessa G, Frank R, Cortese R: Nucleotide sequence of rat liver HMG1 cDNA. Nucleic Acids Res 15: 9077, 1987 Erlandsson Harris H, Andersson U: Minireview: The nuclear protein HMGB1 as a proinflammatory mediator. Eur J Immunol 34: 1503–1512, 2004 Hayakawa K, Arai K, Lo EH: Role of ERK map kinase and CRM1 in IL-1beta-stimulated release of HMGB1 from cortical astrocytes. Glia 58: 1007–1015, 2010 Oh YJ, Youn JH, Ji Y, Lee SE, Lim KJ, Choi JE, Shin JS: HMGB1 is phosphorylated by classical protein kinase C and is secreted by a calcium-dependent mechanism. J Immunol 182: 5800–5809, 2009 Zhang X, Wheeler D, Tang Y, Guo L, Shapiro RA, Ribar TJ, Means AR, Billiar TR, Angus DC, Rosengart MR: Calcium/calmodulindependent protein kinase (CaMK) IV mediates nucleocytoplasmic shuttling and release of HMGB1 during lipopolysaccharide stimulation of macrophages. J Immunol 181: 5015–5023, 2008 Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A, Bianchi ME: Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 22: 5551–5560, 2003 Youn JH, Shin JS: Nucleocytoplasmic shuttling of HMGB1 is regulated by phosphorylation that redirects it toward secretion. J Immunol 177: 7889–7897, 2006 Evankovich J, Cho SW, Zhang R, Cardinal J, Dhupar R, Zhang L, Klune JR, Zlotnicki J, Billiar T, Tsung A: High mobility group box 1 release from hepatocytes during ischemia and reperfusion injury is mediated by decreased histone deacetylase activity. J Biol Chem 285: 39888–39897, 2010 Stros M, Reich J, Kolíbalová A: Calcium binding to HMG1 protein induces DNA
Systemic Inflammatory Response to Renal Insult
535
BRIEF REVIEW
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
536
www.jasn.org
looping by the HMG-box domains. FEBS Lett 344: 201–206, 1994 Stros M, Bernués J, Querol E: Calcium modulates the binding of high-mobility-group protein 1 to DNA. Biochem Int 21: 891–899, 1990 Polianichko AM, Chikhirzhina EV, Andrushchenko VV, Kostyleva EI, Wieser H, Vorob’ev VI: [The effect of Ca2+ ions on DNA compaction in the complex with non-histone chromosomal protein HMGB1]. Mol Biol (Mosk) 38: 701–712, 2004 Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, Rubartelli A: The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep 3: 995–1001, 2002 Park JS, Arcaroli J, Yum HK, Yang H, Wang H, Yang KY, Choe KH, Strassheim D, Pitts TM, Tracey KJ, Abraham E: Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol 284: C870–C879, 2003 Yu M, Wang H, Ding A, Golenbock DT, Latz E, Czura CJ, Fenton MJ, Tracey KJ, Yang H: HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 26: 174–179, 2006 Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, Sohn JW, Yamada S, Maruyama I, Banerjee A, Ishizaka A, Abraham E: High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 290: C917–C924, 2006 Kokkola R, Andersson A, Mullins G, Ostberg T, Treutiger CJ, Arnold B, Nawroth P, Andersson U, Harris RA, Harris HE: RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand J Immunol 61: 1–9, 2005 Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E: Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279: 7370–7377, 2004 Kang R, Tang D, Schapiro NE, Livesey KM, Farkas A, Loughran P, Bierhaus A, Lotze MT, Zeh HJ: The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ 17: 666–676, 2010 El Mezayen R, El Gazzar M, Seeds MC, McCall CE, Dreskin SC, Nicolls MR: Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. Immunol Lett 111: 36–44, 2007 Chen GY, Tang J, Zheng P, Liu Y: CD24 and Siglec-10 selectively repress tissue damageinduced immune responses. Science 323: 1722–1725, 2009 Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ: HMG-1 as a mediator of acute lung inflammation. J Immunol 165: 2950– 2954, 2000
57. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ: HMG-1 as a late mediator of endotoxin lethality in mice. Science 285: 248–251, 1999 58. Li J, Gong Q, Zhong S, Wang L, Guo H, Xiang Y, Ichim TE, Wang CY, Chen S, Gong F, Chen G: Neutralization of the extracellular HMGB1 released by ischaemic damaged renal cells protects against renal ischaemia-reperfusion injury. Nephrol Dial Transplant 26: 469–478, 2011 59. Palumbo R, Sampaolesi M, De Marchis F, Tonlorenzi R, Colombetti S, Mondino A, Cossu G, Bianchi ME: Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol 164: 441–449, 2004 60. Wu H, Ma J, Wang P, Corpuz TM, Panchapakesan U, Wyburn KR, Chadban SJ: HMGB1 contributes to kidney ischemia reperfusion injury. J Am Soc Nephrol 21: 1878– 1890, 2010 61. Chung KY, Park JJ, Kim YS: The role of highmobility group box-1 in renal ischemia and reperfusion injury and the effect of ethyl pyruvate. Transplant Proc 40: 2136–2138, 2008 62. Chen J, John R, Richardson JA, Shelton JM, Zhou XJ, Wang Y, Wu QQ, Hartono JR, Winterberg PD, Lu CY: Toll-like receptor 4 regulates early endothelial activation during ischemic acute kidney injury. Kidney Int 79: 288–299, 2011 63. Lu CY, Hartono J, Senitko M, Chen J: The inflammatory response to ischemic acute kidney injury: A result of the ‘right stuff’ in the ‘wrong place’? Curr Opin Nephrol Hypertens 16: 83–89, 2007 64. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ: High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 192: 565–570, 2000 65. Luan ZG, Zhang H, Yang PT, Ma XC, Zhang C, Guo RX: HMGB1 activates nuclear factor-kB signaling by RAGE and increases the production of TNF-a in human umbilical vein endothelial cells. Immunobiology 215: 956– 962, 2010 66. Zhong TY, Tang J, Liu YW, Li ZJ, Chen DY, Zhao MZ, Wang W, Liu JH, Jiang Y: High mobility group box-1 stimulates proinflammatory cytokine production in endothelial cells via MAP kinases [Article in Chinese]. Nan Fang Yi Ke Da Xue Xue Bao 29: 1517–1520, 2009 67. Treutiger CJ, Mullins GE, Johansson AS, Rouhiainen A, Rauvala HM, ErlandssonHarris H, Andersson U, Yang H, Tracey KJ,
Journal of the American Society of Nephrology
68.
69.
70.
71.
72.
73.
74.
75.
76.
Andersson J, Palmblad JE: High mobility group 1 B-box mediates activation of human endothelium. J Intern Med 254: 375–385, 2003 Tamai K, Yamazaki T, Chino T, Ishii M, Otsuru S, Kikuchi Y, Iinuma S, Saga K, Nimura K, Shimbo T, Umegaki N, Katayama I, Miyazaki J, Takeda J, McGrath JA, Uitto J, Kaneda Y: PDGFRalpha-positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia. Proc Natl Acad Sci U S A 108: 6609–6614, 2011 Kohno T, Anzai T, Naito K, Miyasho T, Okamoto M, Yokota H, Yamada S, Maekawa Y, Takahashi T, Yoshikawa T, Ishizaka A, Ogawa S: Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling. Cardiovasc Res 81: 565–573, 2009 Limana F, Germani A, Zacheo A, Kajstura J, Di Carlo A, Borsellino G, Leoni O, Palumbo R, Battistini L, Rastaldo R, Müller S, Pompilio G, Anversa P, Bianchi ME, Capogrossi MC: Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation. Circ Res 97: e73–e83, 2005 Ranzato E, Patrone M, Pedrazzi M, Burlando B: Hmgb1 promotes wound healing of 3T3 mouse fibroblasts via RAGE-dependent ERK1/2 activation. Cell Biochem Biophys 57: 9–17, 2010 Ranzato E, Patrone M, Pedrazzi M, Burlando B: HMGb1 promotes scratch wound closure of HaCaT keratinocytes via ERK1/2 activation. Mol Cell Biochem 332: 199–205, 2009 Sachdev U, Cui X, Hong G, Namkoong S, Karlsson JM, Baty CJ, Tzeng E: High mobility group box 1 promotes endothelial cell angiogenic behavior in vitro and improves muscle perfusion in vivo in response to ischemic injury. J Vasc Surg 55: 180–191, 2012 Biscetti F, Straface G, De Cristofaro R, Lancellotti S, Rizzo P, Arena V, Stigliano E, Pecorini G, Egashira K, De Angelis G, Ghirlanda G, Flex A: High-mobility group box-1 protein promotes angiogenesis after peripheral ischemia in diabetic mice through a VEGF-dependent mechanism. Diabetes 59: 1496–1505, 2010 Mitola S, Belleri M, Urbinati C, Coltrini D, Sparatore B, Pedrazzi M, Melloni E, Presta M: Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol 176: 12–15, 2006 Wake H, Mori S, Liu K, Takahashi HK, Nishibori M: High mobility group box 1 complexed with heparin induced angiogenesis in a matrigel plug assay. Acta Med Okayama 63: 249–262, 2009
J Am Soc Nephrol 24: 529–536, 2013
