The Uremic Toxin Acrolein Promotes Suicidal Erythrocyte Death

Abstract

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⁺.

Erythrocyte Alterations and Increased Cardiovascular Risk in Chronic Renal Failure

“…As residual renal function declines, this alteration gradually accentuates and is boosted by compounds pathologically present in uremic plasma (24), including beta-2 microglobulin (25), acrolein (26), and indoxyl sulphate (27). Extracorporeal dialysis may reduce the ability of uremic plasma to induce erythrocytes' PS exposure, and this is even more significant 2 Nephrourol Mon.…”

Stimulation of Suicidal Erythrocyte Death by Garcinol

“…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.…”

Stimulation of Suicidal Erythrocyte Death by Naphthazarin

“…Naphthazarin sensitizes breast cancer cells to the pro-apoptotic effect of radiation [6]. Naphthazarin is effective by various cellular mechanisms including oxidative stress [7,8] [13,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] and accelerated eryptosis contributes to the pathophysiology of several clinical conditions, such as iron deficiency, phosphate depletion, malignancy, metabolic syndrome, diabetes, hepatic and renal insufficiency, dehydration, hyperphosphataemia, haemolytic uraemic syndrome, sepsis, malaria, sickle cell disease, thalassaemia and Wilson's disease [13,[34][35][36].The present study explored whether naphthazarin is able to trigger suicidal death of erythrocytes, that is cells devoid of mitochondria and nuclei, key organelles in the execution of apoptosis. To this end, erythrocytes drawn from healthy volunteers were treated with naphthazarin, and phosphatidylserine surface abundance, cell volume, [Ca 2+ ] i , oxidative stress and ceramide abundance were determined.…”

“…Eryptosis could further be triggered by the activation of casein kinase 1a [13], Janus-activated kinase JAK3 [13], protein kinase C [13] or p38 kinase [13], and by inhibition of AMP-activated kinase AMPK [13], cGMP-dependent protein kinase [13], PAK2 kinase [13] or sorafenib/sunitinib-sensitive kinases [13]. Eryptosis may be elicited by a wide variety of chemicals [13,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] and accelerated eryptosis contributes to the pathophysiology of several clinical conditions, such as iron deficiency, phosphate depletion, malignancy, metabolic syndrome, diabetes, hepatic and renal insufficiency, dehydration, hyperphosphataemia, haemolytic uraemic syndrome, sepsis, malaria, sickle cell disease, thalassaemia and Wilson's disease [13,[34][35][36].…”