Uremic Toxicity-Induced Eryptosis and Monocyte Modulation: The Erythrophagocytosis as a Novel Pathway to Renal Anemia

Bonan, Natália Borges; Steiner, Thiago M.; Kuntsevich, Viktoriya; Virzì, Grazia Maria; Azevedo, Marina Luise Viola de; Nakao, Lia S.; Barreto, Fellype Carvalho; Ronco, Claudio; Thijssen, Stephan; Kotanko, Peter; Pecoits‐Filho, Roberto; Moreno-Amaral, Andréa Novais

doi:10.1159/000443784

Cited by 32 publications

(44 citation statements)

References 20 publications

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“…and Bonan et al . [19, 59]. The low level of eryptosis in our population is paralleled by higher levels of hemoglobin and a smaller age difference between controls and HD patients compared to the previous studies.…”

Section: Discussionsupporting

confidence: 59%

“…Noteworthy, in our study the systolic blood pressure decreased on average by 18 mmHg, hence an elevated production of NO in our population may contribute to the low level of PS-exposure. Uremic serum of ESRD patients promotes a pro-inflammatory CD14++/CD16+ monocyte phenotype with increased erythrophagocytosis, promoting an accelerated clearance of PS-exposing RBCs and thus suggesting an additional pathway for renal anemia, without necessarily increasing the number of eryptotic RBCs [59]. …”

Section: Discussionmentioning

confidence: 99%

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Erythrocyte Sodium Sensitivity and Eryptosis in Chronic Hemodialysis Patients

Meyring-Wösten

Kuntsevich

Campos

et al. 2017

Kidney Blood Press Res

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Background/Aims: In hemodialysis (HD) patients the endothelial and erythrocyte glycocalyx is impaired which in turn correlates with elevated erythrocyte sodium sensitivity (ESS). Additionally, apoptotic erythrocyte death (eryptosis), characterized by phosphatidylserine (PS) exposure on the cell surface, is increased in this population. We aimed to explore the relationship of ESS and eryptosis. Methods: Blood samples were collected from 11 healthy controls and 20 chronic HD patients before and after midweek HD. ESS was quantified by the salt blood test. PS-exposure, intracellular reactive oxygen species (ROS) of erythrocytes and reticulocytes were assessed by flow cytometry. Results: Compared to controls ESS was significantly higher in HD patients preHD and did not change during treatment. The percentage of eryptotic cells did not differ between controls and patients preHD. However, eryptosis decreased during HD. ESS and eryptosis were uncorrelated, while eryptosis was positively correlated with intracellular ROS and percent reticulocytes. Conclusions: Higher ESS levels in HD patients indicate a pathologic glycocalyx. ESS and eryptosis were not correlated. The decreased eryptosis postHD may possibly be related to dialytic uremic toxin removal, but is likely multifactorial. The relationship between eryptosis and intracellular ROS warrants further research.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Erythrocyte Sodium Sensitivity and Eryptosis in Chronic Hemodialysis Patients

Meyring-Wösten

Kuntsevich

Campos

et al. 2017

Kidney Blood Press Res

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“…ESA in PD), remained anemic with hemoglobin levels of 10.07 g·dL −1 (HD) and 10.89 g·dL −1 (PD), indicating that anemia is a major complication in CKD . Mounting evidence for a decreased erythrocyte survival in CKD is provided by additional studies .…”

Section: Clinical Conditions Stimulating Eryptosis By Generation Of Omentioning

confidence: 98%

“…Anemia in CKD is often not normalized despite overcompensation of erythropoietin deficiency. Compelling evidence suggests that anemia in CKD is mainly the result of accelerated suicidal erythrocyte death . Although erythropoietin inhibits erythrocyte cation channel activity , its application in CKD is apparently not sufficient to fully compensate anemia.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress, eryptosis and anemia: a pivotal mechanistic nexus in systemic diseases

et al. 2018

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The average lifespan of circulating erythrocytes usually exceeds hundred days. Prior to that, however, erythrocytes may be exposed to oxidative stress in the circulation which could cause injury and trigger their suicidal death or eryptosis. Oxidative stress activates Ca -permeable nonselective cation channels in the cell membrane, thus, stimulating Ca entry and subsequent cell membrane scrambling resulting in phosphatidylserine exposure and activation of Ca -sensitive K channels leading to K exit, hyperpolarization, Cl exit, and ultimately cell shrinkage due to loss of KCl and osmotically driven water. While the mechanistic link between oxidative stress and anemia remains ill-defined, several diseases such as diabetes, hepatic failure, malignancy, chronic kidney disease and inflammation have been identified to display both increased oxidative stress as well as eryptosis. Recent compelling evidence suggests that oxidative stress is an important perpetrator in accelerating erythrocyte loss in different systemic conditions and an underlying mechanism for anemia associated with these pathological states. In the present review, we discuss the role of oxidative stress in reducing erythrocyte survival and provide novel insights into the possible use of antioxidants as putative antieryptotic and antianemic agents in a variety of systemic diseases.

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“…The eryptosis in malignancy is stimulated, at least in part, by a plasma component. The percentage of eryptotic erythrocytes was significantly higher following exposure of healthy Hepatic injury 12,13 Cardiac failure 14 Chronic kidney disease [15][16][17][18] Hemolytic uremic syndrome 1 erythrocytes to plasma from patients with lung cancer than to plasma from healthy individuals. 99 Mechanisms involved in the triggering of eryptosis by lung cancer include oxidative stress and ceramide abundance.…”

Section: Enhanced Eryptosis In Malignancymentioning

confidence: 99%

Suicidal death of erythrocytes in cancer and its chemotherapy: A potential target in the treatment of tumor‐associated anemia

Lang

Bissinger

Qadri

et al. 2017

Intl Journal of Cancer

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In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis characterized by cell shrinkage and cell membrane scrambling. Eryptotic erythrocytes are rapidly cleared from circulating blood and may adhere to the vascular wall. Stimulation of eryptosis thus impairs microcirculation and leads to anemia as soon as the loss of erythrocytes cannot be fully compensated by enhanced erythropoiesis. Signaling stimulating eryptosis includes increase of cytosolic Ca -activity, ceramide, caspases, calpain, p38-kinase, protein-kinase C, Janus-activated kinase 3, casein-kinase 1α, and cyclin-dependent kinase 4. Eryptosis is inhibited by AMP-activated kinase, p21-activated kinase 2, cGMP-dependent protein-kinase, mitogen- and stress-activated kinase, and sorafenib- and sunitinib-sensitive tyrosine-kinases. Eryptosis is triggered by complement, hyperosmotic shock, energy-depletion, oxidative stress, multiple xenobiotics including diverse cytostatic drugs, diabetes, hepatic failure, iron-deficiency, chronic kidney disease, hemolytic-uremic-syndrome, fever, systemic lupus erythematosus, infections, sepsis, sickle cell anemia, thalassemia, glucose-6-phosphate-dehydrogenase deficiency, and Wilson´s disease. Compelling evidence points to a decisive role of eryptosis in anemia of malignancy. As shown for lung cancer, eryptosis inducing plasma components accumulate in cancer patients and trigger oxidative stress and ceramide. The tumor-induced eryptosis leads to anemia despite increased erythropoiesis. The stimulation of eryptosis in malignancy is compounded by cytostatic treatment, as a large number of cytostatic agents trigger eryptosis. Inhibiting eryptosis may be a useful strategy in reducing tumor-induced anemia and impaired microcirculation. Inhibitors of eryptosis may, however, be harmful, if they similarly interfere with death of tumor cells. Clearly, additional experimental effort is required to achieve killing of tumor cells with simultaneous avoidance of stimulated eryptosis.

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Uremic Toxicity-Induced Eryptosis and Monocyte Modulation: The Erythrophagocytosis as a Novel Pathway to Renal Anemia

Cited by 32 publications

References 20 publications

Erythrocyte Sodium Sensitivity and Eryptosis in Chronic Hemodialysis Patients

Erythrocyte Sodium Sensitivity and Eryptosis in Chronic Hemodialysis Patients

Oxidative stress, eryptosis and anemia: a pivotal mechanistic nexus in systemic diseases

Suicidal death of erythrocytes in cancer and its chemotherapy: A potential target in the treatment of tumor‐associated anemia

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