Attenuation of ischemic renal injury with fructose 1,6-diphosphate

Didlake, Ralph; Kirchner, Kent A.; Lewin, Jack R.; Bower, John D.; Markov, Angel K.

doi:10.1016/0022-4804(89)90111-x

Cited by 47 publications

(28 citation statements)

References 15 publications

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“…Our data demonstrate that ATP levels were depleted in hypoxic-LLCPK 1 cells in concordance with reduced GAPDH activity. PARP inhibition preserved ATP levels, suggesting restoration of anaerobic glycolysis by improved GAPDH activity; however, PARP inhibition could not replete ATP levels completely, suggesting that GAPDH may not be the "rate-limiting" enzyme and modulation of other key glycolytic enzymes such as phosphofructokinase or its product, fructose 1,6-biphosphate, 37 may also be involved in the metabolic control of anaerobic ATP synthesis under hypoxic conditions. 34,38 Nevertheless, the significant preservation of energy levels may be sufficient to reduce the necrotic cell death that was revealed by our cytotoxicity experiments.…”

Section: Discussionmentioning

confidence: 98%

PARP-1 Inhibits Glycolysis in Ischemic Kidneys

Devalaraja-Narashimha¹,

Padanilam²

2009

Journal of the American Society of Nephrology

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After ischemic renal injury (IRI), selective damage occurs in the S 3 segments of the proximal tubules as a result of inhibition of glycolysis, but the mechanism of this inhibition is unknown. We previously reported that inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) activity protects against ischemia-induced necrosis in proximal tubules by preserving ATP levels. Here, we tested whether PARP-1 activation in proximal tubules after IRI leads to poly(ADP-ribosyl)ation of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a modification that inhibits its activity. Using in vitro and in vivo models, under hypoxic conditions, we detected poly(ADP-ribosyl)-ation and reduced activity of GAPDH; inhibition of PARP-1 activity restored GAPDH activity and ATP levels. Inhibition of GAPDH with iodoacetate exacerbated ATP depletion, cytotoxicity, and necrotic cell death of LLCPK 1 cells subjected to hypoxic conditions, whereas inhibition of PARP-1 activity was cytoprotective. In conclusion, these data indicate that poly(ADP-ribosyl)ation of GAPDH and the subsequent inhibition of anaerobic respiration exacerbate ATP depletion selectively in the proximal tubule after IRI.

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Section: Discussionmentioning

confidence: 98%

PARP-1 Inhibits Glycolysis in Ischemic Kidneys

Devalaraja-Narashimha¹,

Padanilam²

2009

Journal of the American Society of Nephrology

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“…5 - 6 Deterioration of the cerebral energy state results in loss of intracellular K + , depolarization of the neuronal membrane, and influx of Ca 2+ . 17 The increase in intracellular free Ca 2+ is suggested to precipitate irreversible neuronal damage during ischemia-hypoxia or following reperfusion of ischemic brain by triggering a cascade of events, which may include uncoupling of oxidative phosphorylation, release of neurotransmitters, activation of intracellular enzymes, accumulation of free fatty acids, and generation of oxygen free radicals. 189 Thus, it appears that ATP deficit and subsequent intracellular Ca 2+ accumulation are the two primary factors in the chain of events leading to irreversible brain injury.…”

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confidence: 99%

Prevention of ischemic-hypoxic brain injury and death in rabbits with fructose-1,6-diphosphate.

Farias

Smith

Markov

1990

Stroke

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Fructose-l,6-diphosphate has been shown to improve neurologic recovery following resuscitation from cardiac arrest and to restore brain electrical activity during hypoglycemic coma in rabbits. In view of these findings, we determined whether fructose-1,6-diphosphate protects the brain during ischemia-hypoxia. We subjected 16 rabbits to hypotension, hypoxemia, and bilateral common carotid artery occlusion. Five minutes after the onset of isoelectric electroencephalograms, seven randomly selected rabbits received 10% fructose-l,6-diphosphate (350 mg/kg bolus followed by 10 mg/kg/min infusion for 90 minutes) and the remaining nine rabbits (controls) received an equal volume of 1.5% NaCl (3.5 ml/kg bolus followed by 0.1 ml/kg/min infusion for 90 minutes). After isoelectricity lasting 7.86±0.8 minutes (mean±SEM) in the treated group and 6.44 ±0.38 minutes in the control group, the rabbits were reinfused with autologous shed blood and reoxygenated and the carotid artery occluders were removed. Treated rabbits recovered electrical activity more rapidly than the controls (p<0.005), and all seven treated rabbits survived. Only two controls (22%) survived (p<0.001), and they were severely disabled. Histology showed extensive cortical necrosis and focal necrosis in the hippocampi and cerebellum of brains from the two surviving controls. Brains from two treated rabbits exhibited minimal neuronal loss limited to the neocortex, and the brains from the remaining five treated rabbits were normal. This study suggests that fructose-1,6 -diphosphate protects the brain from ischemic-hypoxic insults.

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“…Phosphofructokinase represents a key enzyme in glycolysis that appears to be inhibited by hypoxia. However, this mechanism presupposes that exogenous FBP enters the cell, whereas only indirect evidence support this possibility (4). Conversely, studies based on [14C]FBP uptake in erythrocytes demonstrated that the compound does not enter the cell (17,18).…”

Section: Resultsmentioning

confidence: 99%

Improvement of Ischemic Myocardial Dysfunction by Nisoldipine in Relation to Its Coronary Vasodilating Action

Trimarchi

Arcadi

Luca

et al. 1993

Japanese Journal of Pharmacology

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ABSTRACT-We examined the protective activity of fructose l,6-bisphosphate (FBP) on mortality and delayed hippocampal cell death induced by transient cerebral ischemia in the Mongolian gerbil. Forebrain ischemia was produced by bilaterally occluding the common carotid arteries for 15 min using micro aneurysm clips; then the blood supply to the brain was restored. The number of survivors was counted for 8 days, and the histopathological damage in the CAI region of the hippocampus was scored according to the semiquantitative scale of Rudolphi and colleagues. When injected 15 min before the ischemic insult, FBP (100 and 333 mg/kg, i.v.) significantly reduced the rate of mortality during the 8-day observation period. Equivalent doses of fructose and fructose monophosphate did not improve survival, and neither did low doses (33 mg/kg) of FBP. FBP also produced a significant degree of protection against the CAI pyramidal cell loss in comparison with its vehicle (distilled water). Conversely, when we administered the compound, at the same dose, 15 min after the release of the arterial occlusion, we observed neither a significant reduc tion of mortality nor significant protection against hippocampal CAI pyramidal cell loss. These results sug gest that FBP possesses salutary properties against the damages induced by transient cerebral ischemia, although they are evident only when the compound is administered before the resolution of the ischemic injury.

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Attenuation of ischemic renal injury with fructose 1,6-diphosphate

Cited by 47 publications

References 15 publications

PARP-1 Inhibits Glycolysis in Ischemic Kidneys

PARP-1 Inhibits Glycolysis in Ischemic Kidneys

Prevention of ischemic-hypoxic brain injury and death in rabbits with fructose-1,6-diphosphate.

Improvement of Ischemic Myocardial Dysfunction by Nisoldipine in Relation to Its Coronary Vasodilating Action

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