TRANSLATIONAL AND CLINICAL MEDICINE - Georgian Medical Journal

Red blood cells (RBC) are the major cell component of blood. Their main function is to transport oxygen and carbon dioxide, however, besides the main function of RBCs have also the ability to transport immune complexes, express numerous adhesion molecules, and influence leukocytes and platelets margination and adhesion. The molecular architecture of cell membranes plays a key role in the determination of their function. Modifications of RBC membrane components could alter RBC functions and rheological properties.  In this review changes in the protein composition and structure of RBCs membranes in diabetes and their possible diagnostic and prognostic significance are considered.

RBCs membrane proteins are categorized in terms of protein function into three groups: cytoskeletal proteins (spectrin, actin, protein 4.1, etc.), integral structural proteins (band 3, glycophorins (GP), etc.), and anchoring proteins (ankyrin, protein 4.2, etc.). The three principal “cytoskeleton proteins” are spectrin (α and β), actin, and protein 4.1, forming the “junctional complex”, that provides support to the lipid bilayer, and maintains the integrity, shape, and architecture of the red blood cell.  The unusual properties of RBC cytoskeletal proteins form specialized ensembles, provide a unique combination of flexibility and stability RBCs membrane controlling their biogenesis, survival, and function. The extracellular domain of heavily glycosylated sialoglycoproteins (glycophorins, bend 3 protein) at physiological pH are conferring a negative surface charge to RBCs membrane, which plays a crucial role in modulating RBC–RBC interactions, their interactions with vascular endothelium and the other circulating blood cells.

Tightly association of several RBCs' membrane proteins disorders with different pathological processes was identified. In diabetes, RBC membranes are affected by chronic exposure to glucose, triggering their biochemical modifications (glycosylation, oxidation), with subsequent structural and functional disruption of the cell (disorders of their deformability, adhesion to the endothelium), which is further involved in the pathogenesis of diabetes and its complications. The alterations of RBCs membrane proteins might be useful sensitive biomarkers for long-term glycemic control, early diagnosis, or monitoring of disease progression.

Pasini E.M., M. Kirkegaard, P. Mortensen, H.U. Lutz, A.W. Thomas and M. Mann, In-depth analysis of the membrane and cytosolic proteome of red blood cells, Blood. 2006, 108(3), 791–801.

de Oliveira S, Carlota S. An. overview about erythrocyte membrane Clinical Hemorheology and Microcirculation. 2010, 44(1), 63–74

Piagnerelli M., K. Zouaoui B, M. Vanhaeverbeek, and Vincent J. L., Red blood cell rheology in sepsis. Intensive Care Medicine, 2003, 29(7),1052–1061.

Zhao Y, Wang X, Wang R, Chen D, Noviana M, Zhu H.J. Nitric oxide inhibits hypoxia-induced impairment of human RBC deformability through reducing the cross-linking of membrane protein band 3. Cell Biochem. 2019. 120(1):305-320.

Thomas T, Stefanoni D, Dzieciatkowska M, Issaian A, Nemkov T, Hill RC, Francis RO, Hudson KE, Buehler PW, Zimring JC, Hod EA, Hansen KC, Spitalnik SL, D'Alessandro A.J Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19 Patients. Proteome Res. 2020. 6;19(11):4455-4469/

Sidorenko SV, Ziganshin RH, Luneva OG, Deev LI, Alekseeva NV, Maksimov GV, Grygorczyk R, Orlov SN.J Proteomics-based identification of hypoxia-sensitive membrane-bound proteins in rat erythrocytes. Proteomics. 2018, 30;184:25-33.

Liu J, Mohandas N, An X.Membrane assembly during erythropoiesis. Curr Opin Hematol. 2011, 18(3):133-8

Steck TL. The otganization of proteins in the human red blood cell membrane. A Review. J Cell Bioliogy. 1974, 62(1), 1-19.

Patra M, Chaitali M, Abhijit C. Probing Conformational Stability and Dynamics of Erythroid and Nonerythroid Spectrin: Effects of Urea and Guanidine Hydrochloride. PLOS ONE 2015, 10(1), e0116991.

Aoki T. A Comprehensive Review of Our Current Understanding of Red Blood Cell (RBC) Glycoproteins. Membranes (Basel), 2017, 7(4), 56.

Pantaleo A., Ferru E., Carta F., Valente E., Pippia P., and Turrini F. Effect of heterozygous beta thalassemia on the phosphowrylative response to Plasmodium falciparum infection, J. Proteomics. 2012, 76, pp. 251-258.

Williamson RC, Toye AM. Glycophorin A: Band 3 aid. Blood Cells Mol Dis. 2008 41(1), 35-43.

Telen M.J., Erythrocyte adhesion receptors: blood group antigens and related molecules, Transfusion Medicine Reviews. 2005, 19(1), 32–44.

Said AS, Rogers SC, Doctor A. Physiologic Impact of Circulating RBC Microparticles upon Blood-Vascular Interactions. Front Physiol. 2018. 12;8, 1120

An X, Salomao M, Guo X, Gratzer W, Mohandas N. Tropomyosin modulates erythrocyte membrane stability. Blood. 2007, 109(3). 1284–1288.

Ferru E., Pantaleo A., Carta F. et al., Thalassemic erythrocytes release microparticles loaded with hemichromes by redox activation of p72Syk kinase. Haematologica, 2014, 99(3), 570–578,

Ferru, E., Giger K., Pantaleo A., et al. Regulation of membrane cytoskeletal interactions by tyrosine phosphorylation of erythrocyte band 3. Blood, 2011,117(22), 5998–6006.

Antonella P, Ferru E, Pau MC, Khadjavi A, Mandili G, Mattè A, Spano A, De Franceschi L, Pippia P, and Turrini F. Research Article Band 3 Erythrocyte Membrane Protein Acts as Redox Stress Sensor Leading to Its Phosphorylation by p72 Syk. Oxidative Medicine and Cellular Longevity. 2016, 2016:6051093.

Pruidze N, Khetsuriani R, Sujashvili R, Ioramashvili I, Arabuli M, Sanikidze T. ALTERATIONS OF PROPERTIES OF RED BLOOD CELLS MEMBRANES PROTEINS OF DIFFERENT AGE AND SEX VOLUNTEERS. Georgian Med News. 2015, 244-245, 110-115.

Yasmina S, Djebara S, Lelubre C, Boudjeltia KZ, Biston P, Piagnerelli M. Alterations of the Erythrocyte Membrane during Sepsis. Critical Care Research and Practicem, 2012;2012:702956

Buys AV., Van Rooy M-J, Soma P, Van Papendorp D, Lipinski B., Etheresia Pretorius. Changes in red blood cell membrane structure in type 2 diabetes: a scanning electron and atomic force microscopy study, Cardiovascular Diabetology, 2013, 12, 25.

Bhise SS, Rao JR, Mahabaleshwar VH, Katyare SS. Compositional alterations in erythrocyte membranes in Type II diabetes Indian Journal of Experimental Biology. 2020 58. 671-679.

Gabunia T, Turabelidze-Robaqidze S, Sujashvili R, Ioramashvili I, Gogebashvili N, Sanikidze T. ALTERATIONS OF RBC MEMBRANE PROTEINS IN DIABETIC PATIENTS WITH AND WITHOUT PERIODONTITIS. Georgian Med News. 2015, 248:39-45.

Petropoulos IK., Margetis P, Antonelou MH., Koliopoulos JX., Gartaganis SP., Margaritis LH., Papassider IS.. Structural alterations of the erythrocyte membrane proteins in diabetic retinopathy Archive for Clinical and Experimental Ophthalmology. 2007, 245(8), 1179-88

Gabreanu G.R., Angelescu S. Erythrocyte membrane in type 2 diabetes mellitus. Discoveries (Craiova). 2016, 4(2): e60.

Singh VP., Bali A, Singh N, Jaggi AS. Advanced Glycation End Products and Diabetic Complications. Korean J Physiol Pharmacol. 2014, 18(1): 1–14.