Ca&lt;sup&gt;2+&lt;/sup&gt; Influx versus Efflux during Eryptosis in Uremic Erythrocytes

Polak−Jonkisz, Dorota; Purzyc, Leszek

doi:10.1159/000341627

Cited by 115 publications

(68 citation statements)

References 7 publications

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“…Accelerated suicidal erythrocyte death may contribute to the anemia of several clinical disorders and eryptosis may be triggered by a wide variety of xenobiotics [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45]. …”

Section: Introductionmentioning

confidence: 99%

The Uremic Toxin Acrolein Promotes Suicidal Erythrocyte Death

Ahmed

Langer

Abed

et al. 2013

Kidney Blood Press Res

149

123

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Background: Anemia is a major complication of end stage renal disease. The anemia is mainly the result of impaired formation of erythrocytes due to lack of erythropoietin and iron deficiency. Compelling evidence, however, points to the contribution of accelerated erythrocyte death, which decreases the life span of circulating erythrocytes. Erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine-exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i). Erythrocytes could be sensitized to cytosolic Ca²⁺ by ceramide. In end stage renal disease, eryptosis may possibly be stimulated by uremic toxins. The present study explored, whether the uremic toxin acrolein could trigger eryptosis. Methods: Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin-V-binding, hemolysis from hemoglobin release, [Ca²⁺]_i from Fluo3-fluorescence, and ceramide from fluorescent antibodies. Results: A 48 h exposure to acrolein (30 － 50 µM) did not significantly modify [Ca²⁺]_i but significantly decreased forward scatter and increased annexin-V-binding. Acrolein further triggered slight, but significant hemolysis and increased ceramide formation in erythrocytes. Acrolein (50 µM) induced annexin-V-binding was significantly blunted in the nominal absence of extracellular Ca²⁺. Acrolein augmented the annexin-V-binding following treatment with Ca²⁺ ionophore ionomycin (1 µM). Conclusion: Acrolein stimulates suicidal erythrocyte death or eryptosis, an effect at least in part due to stimulation of ceramide formation with subsequent sensitisation of the erythrocytes to cytosolic Ca²⁺.

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Section: Introductionmentioning

confidence: 99%

The Uremic Toxin Acrolein Promotes Suicidal Erythrocyte Death

Ahmed

Langer

Abed

et al. 2013

Kidney Blood Press Res

149

123

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“…The concentrations required for the effect are lower than those required to counteract growth of tumor cells [20]. In theory, lower garcinol concentrations may be required for triggering of eryptosis in clinical conditions associated with enhanced eryptosis susceptibility of the erythrocytes, such as dehydration [48], hyperphosphatemia [58] chronic kidney disease (CKD) [40,[61][62][63], hemolytic-uremic syndrome [64], diabetes [65], hepatic failure [66], malignancy [30], sepsis [67], Sickle-cell disease [30], beta-thalassemia [30], Hb-C and G6PD-deficiency [30], as well as Wilsons disease [68]. In those disorders lower garcinol concentrations may be sufficient to trigger eryptosis.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Suicidal Erythrocyte Death by Garcinol

Fazio

Briglia

Faggio

et al. 2015

Cell Physiol Biochem

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Background/Aims: The benzophenone garcinol from dried fruit rind of Garcinia indica counteracts malignancy, an effect at least in part due to stimulation of apoptosis. The proapototic effect of garcinol is attributed in part to inhibition of histone acetyltransferases and thus modification of gene expression. Moreover, garcinol triggers mitochondrial depolarisation. Erythrocytes lack gene expression and mitochondria but are nevertheless able to enter apoptosis-like suicidal death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, energy depletion and Ca 2+ entry with increase of cytosolic Ca 2+ activity ([Ca 2+ ] i ). The present study explored, whether and how garcinol induces eryptosis. Methods: To this end, phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, hemolysis from hemoglobin release, [Ca 2+ ] i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence and cytosolic ATP levels utilizing a luciferin-luciferase-based assay. Results: A 24 hours exposure of human erythrocytes to garcinol (2.5 or 5 µM) significantly increased the percentage of annexin-V-binding cells. Garcinol decreased (at 1 µM and 2.5 µM) or increased (at 5 µM) forward scatter. Garcinol (5 µM) further increased Fluo3-fluorescence, increased DCFDA fluorescence, and decreased cytosolic ATP levels. The effect of garcinol on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca 2+ . Conclusions: Garcinol triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part due to stimulation of ROS formation, energy depletion and Ca 2+ entry.

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“…Several substances inhibit eryptosis [113][114][115][116]. Enhanced eryptosis is observed in diverse clinical conditions including iron deficiency [58], vitamin D excess [117], chronic kidney disease (CKD) [118][119][120][121][122][123], hemolytic-uremic syndrome [124], autoimmune hemolytic anemia [125], diabetes [126], hypertension and dyslipidemia [127], hepatic failure [128], malignancy [129][130][131], arteritis [132], systemic lupus erythematosus [133], sepsis [134,135], malaria [58,136,137], sicklecell disease [58], beta-thalassemia [58], Hb-C and G6PD-deficiency [58], Wilsons disease [134], as well as advanced age [138]. Eryptosis further increases following storage for transfusion [67,68,83,139] and is enhanced in erythrocytes from newborns exposed to oxidative stress [58,140].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Eryptosis by Afatinib

Bhuyan

Läng

2018

Cell Physiol Biochem

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Background/Aims: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor afatinib is primarily utilized for the treatment of non-small cell lung carcinoma. The drug is at least partially effective by triggering suicidal tumor cell death. Side effects of afatinib treatment include anemia. At least in theory, afatinib induced anemia could be secondary to stimulation of suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling potentially stimulating eryptosis include increase of cytosolic Ca 2+ activity ([Ca 2+ ] i ), induction of oxidative stress, and increase of ceramide abundance. The present study explored, whether afatinib induces eryptosis and, if so, whether its effect involves Ca 2+ entry, oxidative stress, and/or ceramide. Methods: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca 2+ ] i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to afatinib (≥ 4 µg/ml) significantly increased the percentage of annexin-V-binding cells and significantly decreased forward scatter. Afatinib significantly increased Fluo3-fluorescence, DCFDA fluorescence and ceramide abundance. The effect of afatinib on annexin-V-binding and forward scatter was significantly blunted by removal of extracellular Ca 2+ . Conclusions: Afatinib triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca 2+ entry, oxidative stress, and ceramide.

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Ca<sup>2+</sup> Influx versus Efflux during Eryptosis in Uremic Erythrocytes

Cited by 115 publications

References 7 publications

The Uremic Toxin Acrolein Promotes Suicidal Erythrocyte Death

The Uremic Toxin Acrolein Promotes Suicidal Erythrocyte Death

Stimulation of Suicidal Erythrocyte Death by Garcinol

Stimulation of Eryptosis by Afatinib

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