Myeloperoxidase Is Critically Involved in the Induction of Organ Damage after Renal Ischemia Reperfusion

Matthijsen, Robert A.; Huugen, Dennis; Hoebers, Nicole; Vries, Bart de; Peutz‐Kootstra, Carine J.; Aratani, Yasuaki; Daha, Mohamed R.; Tervaert, Jan Willem Cohen; Buurman, Wim A.; Heeringa, Peter

doi:10.2353/ajpath.2007.070184

Cited by 109 publications

(82 citation statements)

References 49 publications

(49 reference statements)

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“…56 In contrast, blockade of MPO activity in mouse models and in humans can reduce the pathological response in diseases such as PD and in pathological conditions such as renal ischemia. 11,18 Considering our results in the context of these conflicting reports, it seems that MPO may act with dual functionality, having both pathological and protective functions under abnormal conditions. MPO has been shown to act as a direct and significant mediator of decreased NO bioavailability.…”

Section: Discussionmentioning

confidence: 70%

“…MPO and MPO-derived oxidants could mediate inflammatory responses at sites of inflammation, thereby contributing to the defense system against pathogens. 10 Reports 11,12 indicate that MPO levels are significantly increased in various disease states, such as infection, ischemia, atherosclerosis, and acute myeloid leukemia. Increased MPO levels are widely considered characteristic of systemic inflammatory diseases.…”

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confidence: 99%

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Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Chang

Song

Jeon

et al. 2011

The American Journal of Pathology

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Rotenone exposure has emerged as an environmental risk factor for inflammation-associated neurodegenerative diseases. However, the underlying mechanisms responsible for the harmful effects of rotenone in the brain remain poorly understood. Herein, we report that myeloperoxidase (MPO) may have a potential regulatory role in rotenone-exposed brain-resident immune cells. We show that microglia, unlike neurons, do not undergo death; instead, they exhibit distinctive activated properties under rotenone-exposed conditions. Once activated by rotenone, microglia show increased production of reactive oxygen species, particularly HOCl. Notably, MPO, an HOClproducing enzyme that is undetectable under normal conditions, is significantly increased after exposure to rotenone. MPO-exposed glial cells also display characteristics of activated cells, producing proinflammatory cytokines and increasing their phagocytic activity. Interestingly, our studies with MPO inhibitors and MPO-knockout mice reveal that MPO deficiency potentiates, rather than inhibits, the rotenone-induced activated state of glia and promotes glial cell death. Furthermore, rotenone-triggered neuronal injury was more apparent in co-cultures with glial cells from Mpo ؊/؊ mice than in those from wildtype mice. Collectively, our data provide evidence that MPO has dual functionality under rotenone-exposed conditions, playing a critical regulatory role in modulating pathological and protective events in the brain.

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Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 99%

Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Chang

Song

Jeon

et al. 2011

The American Journal of Pathology

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“…41,43 The impaired leukocyte influx seen in kidneys from both CD47 2/2 mice (and WT mice treated with a CD47 blocking antibody) may be in part as a consequence of reduced proinflammatory cytokine and chemokine levels (particularly CXCL2), and may account for the lower degree of renal dysfunction and tissue damage compared with WT controls. Arguing against a primary role for inflammatory cells in CD47 promotion of renal IRI are results obtained in chimera mice.…”

Section: Discussionmentioning

confidence: 99%

Activation of Parenchymal CD47 Promotes Renal Ischemia-Reperfusion Injury

Rogers

Thomson

Isenberg

2012

Journal of the American Society of Nephrology

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Ischemia-reperfusion injury (IRI) contributes to decreased allograft function and allograft rejection in transplanted kidneys. Thrombospondin-1 is a stress protein typically secreted in response to hypoxia and the ligand activator for the ubiquitously expressed receptor CD47. The function of activated CD47 in IRI remains completely unknown. Here, we found that both CD47 and its ligand thrombospondin-1 were upregulated after renal IRI in mice. CD47-knockout mice were protected against renal dysfunction and tubular damage, suggesting that the development of IRI requires intact CD47 signaling. Chimeric CD47-knockout mice engrafted with wild-type hematopoietic cells had significantly lower serum creatinine and less tubular damage than wild-type controls after IRI, suggesting that CD47 signaling in parenchymal cells predominantly mediates renal damage. Treatment with a CD47-blocking antibody protected mice from renal dysfunction and tubular damage compared with an isotype control. Taken together, these data imply that CD47 on parenchymal cells promotes injury after renal ischemia and reperfusion. Therefore, CD47 blockade may have therapeutic potential to prevent or suppress ischemia-reperfusion-mediated damage.

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“…32 MPO was significantly elevated in the saline IR group 24 hours after 45-minute ischemia ( Figure 9C). The increase in MPO was completely prevented by SS-31, suggesting that SS-31 can prevent the IR-mediated inflammatory response.…”

Section: Ss-31 Limited Ir-mediated Inflammatory Responsementioning

confidence: 91%

Mitochondria-Targeted Peptide Accelerates ATP Recovery and Reduces Ischemic Kidney Injury

Szeto

Liu

Soong

et al. 2011

Journal of the American Society of Nephrology

260

244

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The burst of reactive oxygen species (ROS) during reperfusion of ischemic tissues can trigger the opening of the mitochondrial permeability transition (MPT) pore, resulting in mitochondrial depolarization, decreased ATP synthesis, and increased ROS production. Rapid recovery of ATP upon reperfusion is essential for survival of tubular cells, and inhibition of oxidative damage can limit inflammation. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge mitochondrial ROS and inhibit MPT, suggesting that it may protect against ischemic renal injury. Here, in a rat model of ischemia-reperfusion (IR) injury, treatment with SS-31 protected mitochondrial structure and respiration during early reperfusion, accelerated recovery of ATP, reduced apoptosis and necrosis of tubular cells, and abrogated tubular dysfunction. In addition, SS-31 reduced medullary vascular congestion, decreased IR-mediated oxidative stress and the inflammatory response, and accelerated the proliferation of surviving tubular cells as early as 1 day after reperfusion. In summary, these results support MPT as an upstream target for pharmacologic intervention in IR injury and support early protection of mitochondrial function as a therapeutic maneuver to prevent tubular apoptosis and necrosis, reduce oxidative stress, and reduce inflammation. SS-31 holds promise for the prevention and treatment of acute kidney injury. Acute kidney injury (AKI) develops in 5% of hospitalized patients and is associated with significant morbidity. Ischemia is the most common cause of AKI. Despite our current knowledge of the pathophysiology underlying renal ischemia-reperfusion (IR) injury, pharmacologic interventions have not reduced the mortality and morbidity associated with AKI.Rapid recovery of ATP after ischemia is essential for cell survival after IR injury. A profound reduction in intracellular ATP occurs early after onset of ischemia and leads to cytoskeletal derangements, membrane alterations, and cell death by apoptosis and necrosis. 1 Disruption of the cytoskeleton leads to redistribution of integrins and Na ϩ ,K ϩ -ATPase from the basal membrane, resulting in detachment of viable cells from the basement membrane and impairment of Na ϩ reabsorption. The mode of cell death depends on the duration of ischemia and the region of the nephron. Cell death is usually restricted to the outer medullary region where oxygen tension drops precipitously at the corticomedullary junction. 2 The proximal tubules are particularly susceptible to IR injury because they have minimal glycolytic capacity and must rely on mitochondrial metabolism for ATP synthesis. [3][4][5] Ischemia causes damage to all components of the mitochondrial electron transport chain (ETC), resulting in decreased oxidative phosphorylation upon reperfusion. 6 In addition, mitochondria are the primary source of reactive oxygen species (ROS). 6,7 Mitochondria can undergo further damage upon reperfusion because of mitochondrial permeability transition (MPT). During ischemia, elevated mitocho...

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Myeloperoxidase Is Critically Involved in the Induction of Organ Damage after Renal Ischemia Reperfusion

Cited by 109 publications

References 49 publications

Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Activation of Parenchymal CD47 Promotes Renal Ischemia-Reperfusion Injury

Mitochondria-Targeted Peptide Accelerates ATP Recovery and Reduces Ischemic Kidney Injury

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