The Effect of Urea on Sickling

May, Anna; Huehns, E. R.

doi:10.1111/j.1365-2141.1975.tb00513.x

Cited by 9 publications

(2 citation statements)

References 15 publications

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“…Urea also probably affects the hydrophobic bonds within the HbS molecules that result in polymerisation (Nalbandian et al, 1972;May and Huehns, 1975). As such, it has been proposed as a possible treatment for SCA patients (McCurdy and Mahmood, 1971).…”

Section: Discussionmentioning

confidence: 99%

Pathophysiological Relevance of Renal Medullary Conditions on the Behaviour of Red Cells From Patients With Sickle Cell Anaemia

Wadud

Hannemann

et al. 2021

Front. Physiol.

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Red cells from patients with sickle cell anaemia (SCA) contain the abnormal haemoglobin HbS. Under hypoxic conditions, HbS polymerises and causes red cell sickling, a rise in intracellular Ca2+ and exposure of phosphatidylserine (PS). These changes make sickle cells sticky and liable to lodge in the microvasculature, and so reduce their lifespan. The aim of the present work was to investigate how the peculiar conditions found in the renal medulla – hypoxia, acidosis, lactate, hypertonicity and high levels of urea – affect red cell behaviour. Results show that the first four conditions all increased sickling and PS exposure. The presence of urea at levels found in a healthy medulla during antidiuresis, however, markedly reduced sickling and PS exposure and would therefore protect against red cell adherence. Loss of the ability to concentrate urine, which occurs in sickle cell nephropathy would obviate this protective effect and may therefore contribute to pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Pathophysiological Relevance of Renal Medullary Conditions on the Behaviour of Red Cells From Patients With Sickle Cell Anaemia

Wadud

Hannemann

et al. 2021

Front. Physiol.

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“…Urea has further been shown to activate ras (74) and phosphatidylinositol 3-kinase (85) and to modify several further transport processes including the Na ϩ -K ϩ -ATPase, KCl cotransport, and Na ϩ -K ϩ -2Cl Ϫ cotransport (34,35,53,71). The related hydroxy-urea protects erythrocytes against oxidative stress (1) and counteracts the sickling of erythrocytes (4,18,58). Sickle cell anemia sensitizes erythrocytes to the scrambling effect of osmotic shock, oxidative stress, and energy depletion (44).…”

Section: Discussionmentioning

confidence: 98%

Effect of osmotic shock and urea on phosphatidylserine scrambling in thrombocyte cell membranes

Gatidis

Föller

Läng

2010

American Journal of Physiology-Cell Physiology

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Blood passing the renal medulla enters a strongly hypertonic environment challenging functional properties and survival of blood cells. In erythrocytes, exposure to hyperosmotic shock stimulates Ca(2+) entry and ceramide formation with subsequent cell membrane scrambling, an effect partially reversed by high concentrations of Cl(-) or urea. Cell membrane scrambling with phosphatidylserine exposure is part of the procoagulant phenotype of platelets. Coagulation in the hypertonic renal medulla would jeopardize blood flow in the vasa recta. The present study thus explored whether hypertonic environment and urea modify phosphatidylserine exposure of human platelets. FACS analysis was employed to estimate cytosolic Ca(2+) activity with Fluo3 fluorescence, ceramide formation, P-selectin, and glycoprotein IIb/IIIa activation with fluorescent antibodies and phosphatidylserine exposure with annexin V-binding. The spontaneous platelet aggregation was measured by impedance aggregometry. Hyperosmotic shock (addition of 500 mM sucrose or 250 mM NaCl) significantly enhanced cytosolic Ca(2+) activity, ceramide formation, phosphatidylserine exposure, platelet degranulation, and aggregability. Addition of 500 mM urea to isotonic saline did not significantly modify cytosolic Ca(2+) activity, ceramide abundance, or annexin V-binding but significantly blunted the respective effects of hypertonic shock following addition of 500 mM sucrose. In isotonic solutions, both ceramide (20 microM) and Ca(2+) ionophore ionomycin (0.5 microM) increased annexin V-binding, effects again significantly blunted by 500 mM urea. Moreover, oxidative stress by addition of 0.5 mM peroxynitrite increased cytosolic Ca(2+) activity and triggered annexin V-binding, effects again blunted in the presence of 500 mM urea. The observations reveal that hyperosmotic shock and oxidative stress trigger a procoagulant platelet phenotype, an effect blunted by the presence of high urea concentrations.

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Inhibition of Sickle Hemoglobin Polymerization as a Basis for Therapeutic Approaches to Sickle‐Cell Anemia

Noguchi

Schechter

Haley³

et al. 2003

Burger's Medicinal Chemistry and Drug Discovery

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This chapter reviews current understanding of the molecular and cellular basis of the pathophysiology of sickle‐cell anemia, with emphasis on the biophysics of the intracellular polymerization of sickle hemogobin. Factors that modify the severity of the disease manifestations, primarily by altering polymerization tendency, are discussed. This framework is used to present an overview of the major rational approaches to the therapy of sickle‐cell anemia based on inhibiting polymerization with agents that affect either the hemoglobin molecule or the sickle erythrocyte. Discussion of agents that may decrease vascular entrapment of sickle erythrocytes is also presented. Detailed review of the most important current approaches to therapy—pharmacologically elevating fetal hemoglobin—focuses primarily on hydroxyurea, the only drug currently FDA approved for treating sickle‐cell anemia. A brief discussion of other approaches, including stem cell transplantation and gene therapy, concludes the chapter.

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The Effect of Urea on Sickling

Cited by 9 publications

References 15 publications

Pathophysiological Relevance of Renal Medullary Conditions on the Behaviour of Red Cells From Patients With Sickle Cell Anaemia

Pathophysiological Relevance of Renal Medullary Conditions on the Behaviour of Red Cells From Patients With Sickle Cell Anaemia

Effect of osmotic shock and urea on phosphatidylserine scrambling in thrombocyte cell membranes

Inhibition of Sickle Hemoglobin Polymerization as a Basis for Therapeutic Approaches to Sickle‐Cell Anemia

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