Reduction of Ischemia–Reperfusion Injury in the Rat Kidney by FTY720, a Synthetic Derivative of Sphingosine

Delbridge, Michael S.; Shrestha, Badri Man; Raftery, Andrew T.; Nahas, A. Meguid El; Haylor, J.

doi:10.1097/01.tp.0000269794.74990.da

Cited by 34 publications

(24 citation statements)

References 45 publications

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“…The strong antiapoptotic effect of FTY720 was accompanied by a high number of proliferating tubular cells on posttransplant day 7, perhaps reflecting a more robust recovery. Similar to our findings, FTY720 exerted potent antiapoptotic properties and enhanced postischemic tubular cell proliferation as measured by PCNA staining in a rat model of warm renal ischemia (19).…”

Section: Discussionsupporting

confidence: 86%

Cytoprotective Actions of FTY720 Modulate Severe Preservation Reperfusion Injury in RatRenal Transplants

Fuller¹,

Hoff²,

Kong³

et al. 2010

Transplantation

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Section: Discussionsupporting

confidence: 86%

Cytoprotective Actions of FTY720 Modulate Severe Preservation Reperfusion Injury in RatRenal Transplants

Fuller¹,

Hoff²,

Kong³

et al. 2010

Transplantation

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“…33 The cell regeneration marker proliferating cell nuclear antigen (PCNA) increases as early as 24 hours after reperfusion. 34,35 In this study, PCNA-positive (PCNA ϩ ) cells were few in renal sections obtained from the Sham group ( Figure 10A). A small increase in PCNA ϩ nuclei was observed in the saline IR group at 24 hours ( Figure 10 …”

Section: Ss-31 Accelerated Tubular Regenerationmentioning

confidence: 99%

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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“…Sphingosine-1 phosphate receptor agonist, fingolimod, while currently well known for its therapeutic benefit in multiple sclerosis patients, has been previously described to act as a protecting agent from ischemia-reperfusion in the liver [97,98] and kidney [99,100] and, most recently, in murine models of ischemic stroke, demonstrating a reduction in infarct size, better functional neurological outcomes, decreased edema and a decreased number of activated immune cells [101]. Its mechanism of protection is thought to be mediated through its effects on the regulation of cytoskeletal organization, adhesion and migration, proliferation, inflammation and, finally, apoptosis, doing so through its ability to act as an agonist of 5 G-protein-coupled receptors termed S1P 1-5 [102] · These receptors, when activated, have been shown to reduce both hypoxic damage as well as ischemia-reperfusion injury in the cardiac system [103,104].…”

Section: Neuroprotective Strategiesmentioning

confidence: 99%

Ischemia-Reperfusion Injury in Stroke

2012

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Despite ongoing advances in stroke imaging and treatment, ischemic and hemorrhagic stroke continue to debilitate patients with devastating outcomes at both the personal and societal levels. While the ultimate goal of therapy in ischemic stroke is geared towards restoration of blood flow, even when mitigation of initial tissue hypoxia is successful, exacerbation of tissue injury may occur in the form of cell death, or alternatively, hemorrhagic transformation of reperfused tissue. Animal models have extensively demonstrated the concept of reperfusion injury at the molecular and cellular levels, yet no study has quantified this effect in stroke patients. These preclinical models have also demonstrated the success of a wide array of neuroprotective strategies at lessening the deleterious effects of reperfusion injury. Serial multimodal imaging may provide a framework for developing therapies for reperfusion injury.

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Reduction of Ischemia–Reperfusion Injury in the Rat Kidney by FTY720, a Synthetic Derivative of Sphingosine

Abstract: Treatment with FTY720 reduced IRI and prevented unrecoverable acute renal failure after significant ischemic injury. This study suggests that FTY720 may help improve the quality of grafts from NHBD and marginal donors by abrogating the IRI insult.

Cited by 34 publications

References 45 publications

Cytoprotective Actions of FTY720 Modulate Severe Preservation Reperfusion Injury in RatRenal Transplants

Cytoprotective Actions of FTY720 Modulate Severe Preservation Reperfusion Injury in RatRenal Transplants

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

Ischemia-Reperfusion Injury in Stroke

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