ГИПЕРГОМОЦИСТЕИНЕМИЯ И КАРДИОРЕНАЛЬНЫЙ АНЕМИЧЕСКИЙ СИНДРОМ ПРИ САХАРНОМ ДИАБЕТЕ

Нарушения метаболизма гомоцистеина ассоциированы с поражением почек и анемией, что вносит дополнительный вклад в формирование микро- и макроангиопатий, являющихся основной причиной инвалидизации и смерти больных с сахарным диабетом (СД). Однако далеко не все аспекты взаимосвязи гипергомоцистеинемии (ГГЦ) и кардиоренального анемического синдрома при патологии углеводного обмена очевидны, поэтому изучение роли и условий реализации эффектов гомоцистеина приобретает особую значимость. В настоящем обзоре рассмотрены патогенетические связи нарушений метаболизма данной аминокислоты с сосудистыми осложнениями, поражением почек и анемией при СД. На основе анализа экспериментальных и клинических исследований последних лет суммированы данные о молекулярно-биологических аспектах влияния ГГЦ на иммунокомпетентные клетки и компоненты ренин-ангиотензин-альдостероновой системы, роли свободнорадикального окисления, дефицита витаминов и анемии в реализации эффектов гомоцистеина при кардиоренальном анемическом синдроме у пациентов с СД. Обосновано и сформулировано с позиций клинической значимости направление дальнейших исследований. Усовершенствовано патогенетическое обоснование данной проблемы, что открывает новые направления поиска диагностических и терапевтических стратегий при ГГЦ и кардиоренальном анемическом синдроме у пациентов с СД.

гипергомоцистеинемия, кардиоренальный анемический синдром, сахарный диабет, диабетическая нефропатия, анемия

1. Selvin E, Rawlings A.M, Lutsey P et al. Fructosamine and Glycated Albumin and the Risk of Cardiovascular Outcomes and Death. Circulation 2015; 28. In press

2. Aso Y. Cardiovascular disease in patients with diabetic nephropathy. Curr Mol Med 2008; 8 (6): 533-543

3. Mao S, Xiang W, Huang S, Zhang A. Association between homocysteine status and the risk of nephropathy in type 2 diabetes mellitus. Clin Chim Acta 2014; 431: 206-210

4. Wang G, Dai J, Mao et al. Folic acid reverses hyper-responsiveness of LPS-induced chemokine secretion from monocytes in patients with hyperhomocysteinemia. Atherosclerosis 2005; 179 (2): 395-402

5. Смирнов А.В, Добронравов В.А, Голубев Р.В. и др. Распространенность гипергомоцистеинемии в зависимости от стадии хронической болезни почек. Нефрология 2005; 9 (2): 48-52

6. Ruan L, Chen W, Srinivasan S.R. et al. Plasma homocysteine is adversely associated with glomerular filtration rate in asymptomatic black and white young adults: the Bogalusa heart study. Eur J Epidemiol 2009; 24 (6): 315-319

7. Steed M.M, Tyagi S.C. Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxid Redox Signal 2011; 15 (7): 1927-1943

8. Nakagawa T, Tanabe K, Croker B.P. et al. Endothelial dysfunction as a potential contributor in diabetic nephropathy. Nat Rev Nephrol 2011; 7 (1): 36-44

9. Cмирнов А.В, Петрищев Н.Н, Мнускина М.М. и др. Дисфункция эндотелия и апоптоз на ранних стадиях хронической болезни почек. Тер арх 2012; 84(6): 9-15

10. Hohenstein B, Hugo C.P, Hausknecht B. et al. Analysis of NO-synthase expression and clinical risk factors in human diabetic nephropathy. Nephrol Dial Transplant 2008; 23 (4): 1346-1354

11. Sugimoto H, Shikata K, Matsuda M. et al. Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy. Diabetologia 1998; 41 (12): 1426-1434

12. Nakagawa T, Sato W, Glushakova O. et al. Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J Am Soc Nephrol 2007; 18 (2): 539-550

13. Leung T.M, Tipoe G.L, Liong E.C. et al. Endothelial nitric oxide synthase is a critical factor in experimental liver fibrosis. Int J Exp Pathol 2008; 89 (4): 241-250

14. Малахов В.А, Завгородняя А.Н, Лычко В.С. и др. Проблема оксиду азоту в неврології: Монографія. Вид-во СумДПУ ім. А.С. Макаренка, Суми, 2009; 83-84

15. Иванов Н.В, Фогт С.Н, Худякова Н.В. Артериальная гипертензия с позиций нейроиммуноэндокринологии. Артериальная гипертензия 2014; 20 (5): 349-354

16. Faraci F.M. Hyperhomocysteinemia: a million ways to lose control. Arterioscler Thromb Vasc Biol 2003; 23 (3): 371-373

17. Худякова Н.В, Шишкин А.Н, Пчелин И.Ю, Иванов Н.В. Механизмы влияния эстрогенов на сердечно-сосудистую систему. Вестн. С.-Петерб. ун-та Сер 11 2015; (1): 13-24

18. Agrawal N.K, Kant S. Targeting inflammation in diabetes: Newer therapeutic options. World J Diabetes 2014; 5(5): 697-710

19. Zhang D, Fang P, Jiang X et al. Severe hyperhomocysteinemia promotes bone marrow-derived and resident inflammatory monocyte differentiation and atherosclerosis in LDLr/ CBS-deficient mice. Circ Res 2012; 111 (1): 37-49

20. Martinez F.O, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol 2006; 177 (10): 7303-7311

21. Meng S, Ciment S, Jan M et al. Homocysteine induces inflammatory transcriptional signaling in monocytes. Front Biosci (Landmark Ed) 2013; 18: 685-695

22. Odobasic D, Kitching A.R, Tipping P.G, Holdsworth S.R. CD80 and CD86 costimulatory molecules regulate crescentic glomerulonephritis by different mechanisms. Kidney Int 2005; 68(2): 584-594

23. Jude E.B, Douglas J.T, Anderson S.G. et al. Circulating cellular adhesion molecules ICAM-1, VCAM-1, P- and E-selectin in the prediction of cardiovascular disease in diabetes mellitus. Eur J Intern Med 2002; 13 (3): 185-189

24. Albertini J.P, Valensi P, Lormeau B et al. Elevated concentrations of soluble E-selectin and vascular cell adhesion molecule-1 in NIDDM. Effect of intensive insulin treatment. Diabetes Care 1998; 21 (6): 1008-1013

25. Nakamura K, Yamagishi S, Adachi H. et al. Serum levels of soluble form of receptor for advanced glycation end products (sRAGE) are positively associated with circulating AGEs and soluble form of VCAM-1 in patients with type 2 diabetes. Microvasc Res 2008; 76 (1): 52-56

26. Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond) 2013; 124 (3): 139-152

27. Hirano T, Akira S, Taga T, Kishimoto T. Biological and clinical aspects of interleukin 6. Immunol Today 1990; 11 (12): 443-449

28. Horii X Muraguchi A, Iwano M et al. Involvement of IL-6 in mesangial proliferative glomerulonephritis. J Immunol 1989; 143 (12): 3949-3955

29. Kitamura A, Hasegawa G, Obayashi H. et al. Interleukin-6 polymorphism (-634C/G) in the promotor region and the progression of diabetic nephropathy in type 2 diabetes. Diabet Med 2002; 19 (12): 1000-1005

30. Zikou X, Tellis C.C, Rousouli K. et al. Differential membrane expression of Toll-like receptors and intracellular cytokine induction in peripheral blood monocytes of patients with chronic kidney disease and diabetic nephropathy. Nephron Clin Pract 2014; 128 (3-4): 399-406

31. Ishihara K, Hirano T. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 2002; 13 (4-5): 357-368

32. Suzuki D, Miyazaki M, Naka R et al. In situ hybridization of interleukin 6 in diabetic nephropathy. Diabetes 1995; 44 (10): 1233-1238

33. Imaizumi T, Itaya H, Fujita K et al. Expression of tumor necrosis factor-alpha in cultured human endothelial cells stimulated with lipopolysaccharide or interleukin-1alpha. Arterioscler Thromb Vasc Biol 2000; 20 (2): 410-415

34. Nakamura A, Johns E.J, Imaizumi A. et al. Effect of beta(2)-adrenoceptor activation and angiotensin II on tumour necrosis factor and interleukin 6 gene transcription in the rat renal resident macrophage cells. Cytokine 1999; 11 (10): 759-765

35. Noels H, Bernhagen J, Weber C. Macrophage migration inhibitory factor: a noncanonical chemokine important in atherosclerosis. Trends Cardiovasc Med 2009; 19 (3): 76-86

36. Vaidya V.S, Niewczas M.A, Ficociello L.H. et al. Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers, kidney injury molecule-1, and N-acetyl-v-D-glucosaminidase. Kidney Int 2011; 79 (4): 464-470

37. Nguyen G, Delarue F, Burckij C et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109 (11): 1417-1427

38. Becher U.M, Endtmann C, Tiyerili V. et al. Endothelial damage and regeneration: the role of the renin-angiotensin-aldosterone system. Curr Hypertens Rep 2011; 13 (1): 86-92

39. Huang X Noble N.A, Zhang J. et al. Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int 2007; 72 (1): 45-52

40. Топчій I.I, Денисенко В.П, Несен А.О. Стан гемодинаміки та показників активності ферменту АПФ незалежного шляху утворення ангіотензину II у хворих нацукровий діабет із артеріальною гіпертензію та нефропатією в динаміці лікування карділолом та кардіталом. Мистецтво лікування 2003; (6): 55-60

41. Levick S.P, Meluendez G.C, Plante E. et al. Cardiac mast cells: the centrepiece in adverse myocardial remodelling. Cardiovasc Res 2011; 89 (1): 12-19

42. Fujimi K, Uehara X Abe S. et al. Homocysteine-induced oxidative stress upregulates chymase in mouse mastocytoma cells. Hypertens Res 2010; 33 (2): 149-154

43. Топчий И.И. Воспалительный компонент при диабетической нефропатии - новые возможности в ренопротекции? Український тер журн 2005; (1): 93-99

44. Sen U, Herrmann M, Herrmann W, Tyagi S.C. Synergism between AT1 receptor and hyperhomocysteinemia during vascular remodeling. Clin Chem Lab Med 2007; 45 (12): 1771-1776

45. Burns K.D. Angiotensin II and its receptors in the diabetic kidney. Am J Kidney Dis 2000; 36 (3): 449-467

46. Vacek T.P, Rehman S, Neamtu D, et al. Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms. Vasc Health Risk Manag 2015; 11: 173-183

47. Sen U, Rodriguez W.E, Tyagi N. et al. Ciglitazone, a PPAR-gamma agonist, ameliorates diabetic nephropathy in part through homocysteine clearance. Am J Physiol Endocrinol Metab 2008; 295 (5): E1205-E1212

48. Solini A, Santini E, Nannipieri M, Ferrannini E. High glucose and homocysteine synergistically affect the metalloproteinases-tissue inhibitors of metalloproteinases pattern, but not TGFв expression, in human fibroblasts. Diabetologia 2006; 49 (10): 2499-2506

49. Ferrara N, Gerber H.P, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9 (6): 669-676

50. Pushpakumar S.B, Kundu S, Metreveli N, Sen U. Folic acid mitigates angiotensin-II-induced blood pressure and renal remodeling. PLoS One 2013; 8 (12): e83813

51. Hajitou A, Grignet C, Devy L et al. The antitumoral effect of endostatin and angiostatin is associated with a down-regulation of vascular endothelial growth factor expression in tumor cells. FASEB J 2002; 16 (13): 1802-1804

52. Advani A, Kelly D.J, Advani S.L. et al. Role of VEGF in maintaining renal structure and function under normotensive and hypertensive conditions. Proc Natl Acad Sci U S A 2007; 104 (36): 14448-14453

53. McGarrigle S.A, O’Neill S, Walsh G.M. et al. Integrin 6(ИЬ) в3 exists in an activated state in subjects with elevated plasma homocysteine levels. Platelets 2011; 22 (1): 65-73

54. Anders H.J, Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int 2011; 80 (9): 915-925

55. Kreider T, Anthony R.M, Urban J.F. Jr, Gause W.C. Alternatively activated macrophages in helminth infections. Curr Opin Immunol 2007; 19 (4): 448-453

56. Bouhlel M.A, Derudas B, Rigamonti E. et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 2007; 6 (2): 137-143

57. Yideng J, Zhihong L, Jiantuan X. et al. Homocysteine mediated PPARalpha, gamma DNA methylation and its potential pathogenic mechanism in monocytes. DNA Cell Biol 2008; 27 (3): 143-150

58. Tang S.C, Yiu W.H, Lin M, Lai K.N. Diabetic nephropathy and proximal tubular damage. J Ren Nutr 2015; 25 (2): 230-233

59. Монастырская Е.А, Лямина О.Т, Малышев И.Ю. М1 и М2 фенотипы активированных макрофагов и их роль в иммунном ответе и патологии. Патогенез 2008; 6 (4): 31-39

60. Lee F.T, Cao Z, Long D.M. et al. Interactions between angiotensin II and NF-kappaB-dependent pathways in modulating macrophage infiltration in experimentaldiabetic nephropathy. J Am Soc Nephrol 2004; 15 (8): 2139-2151

61. Hwang S.X, Woo C.W, Au-Yeung K.K. et al. Homocysteine stimulates monocyte chemoattractant protein-1 expression in the kidney via nuclear factor-kappaB activation. Am J Physiol Renal Physiol 2008; 294 (1): F236-F244

62. Kumagai H, Katoh S, Hirosawa K et al. Renal tubulointerstitial injury in weanling rats with hyperhomocysteinemia. Kidney Int 2002; 62 (4): 1219-1228

63. Ingram A.J, Krepinsky J.C, James L et al. Activation of mesangial cell MAPK in response to homocysteine. Kidney Int 2004; 66 (2): 733-745

64. Kumar A, Hawkins K.S, Hannan M.A, Ganz M.B. Activation of PKC-beta (I) in glomerular mesangial cells is associated with specific NF-kappaB subunit translocation. Am J Physiol Renal Physiol 2001; 281 (4): F613-F619

65. Пчелин И.Ю, Шишкин А.Н. Механизмы развития и клиническое значение анемии у пациентов с сахарным диабетом 1 и 2 типа. Вестн С.-Петерб ун-та Сер 11 2010; (2): 73-80

66. Sinclair K.D, Allegrucci C, Singh R. et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci U S A 2007; 104 (49): 19351-19356

67. Solomon L.R. Functional cobalamin (vitamin B12) deficiency: role of advanced age and disorders associated with increased oxidative stress. Eur J Clin Nutr 2015; 69 (6): 687-692

68. Wang X, Wang G, Zhang F.C. et al. Folic acid attenuates homocysteine induced human monocytes chemokine secretion via reducing NADPHoxidase activity [abstract]. Zhonghua Xin Xue Guan Bing Za Zhi 2007; 35 (10): 956-959

69. Yang H.T, Lee M, Hong K.S. et al. Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials. Eur J Intern Med 2012; 23 (8): 745-754

70. Brattstnjm L, Wilcken D.E. Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr 2000; 72 (2): 315-323

71. Baggott J.E, Tamura T. Homocysteine, iron and cardiovascular disease: a hypothesis. Nutrients 2015; 7 (2): 1108-1118

72. Mattioli A.V, Bonetti L, Zennaro M. et al. Acute myocardial infarction in young patients: nutritional status and biochemical factors. Int J Cardiol 2005; 101 (2): 185-190

73. Schiepers O.J.G, Durga J. Response to Baggott and Tamura: «Serum iron parameters and plasma total homocysteine concentrations». J Gerontol A Biol Sci Med Sci 2011; 66A: 657-658

74. Arezes J, Nemeth E. Hepcidin and iron disorders: new biology and clinical approaches. Int J Lab Hematol 2015; 37 [Suppl 1]: 92-98

75. Ganz T Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003; 102 (3): 783-788

76. Makhro A, Wang J, Vogel J. et al. Functional NMDA receptors in rat erythrocytes. Am J Physiol Cell Physiol 2010; 298 (6): C1315-C1325

77. Acharya U, Gau J.T, Horvath W. et al. Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature. J Hematol Oncol 2008; 1: 26

78. Zittan E, Preis M, Asmir I et al. High frequency of vitamin B12 deficiency in asymptomatic individuals homozygous to MTHFR C677T mutation is associated with endothelial dysfunction and homocysteinemia. Am J Physiol Heart Circ Physiol 2007; 293 (1): H860-H865

79. Cai B, Li X, Wang Y. et al. Apoptosis of bone marrow mesenchymal stem cells caused by homocysteine via activating JNK signal. PLoS One 2013; 8 (5): e63561