Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC21310.15690/vramn.v68i2.547ENDOCRINOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ЭНДОКРИНОЛОГИИROLE OF CIRCULATING ANGIOGENIC FACTORS IN DIABETIC KIDNEY DISEASEРОЛЬ ЦИРКУЛИРУЮЩИХ АНГИОГЕННЫХ ФАКТОРОВ В ПОРАЖЕНИИ ПОЧЕК ПРИ САХАРНОМ ДИАБЕТЕMartynovS. A.МартыновС. А.
Russian Federation

PhD, Leading Research Worker, Endocrinology Research Center Address: 117036, Moscow, Dmitriya Ul’yanova St., 11; tel: (495) 500-01-45

smartynov@inbox.ruShestakovaM. V.ШестаковаМ. В.
Russian Federation

RAMS cor. member, PhD, Professor, Director of Diabetes Institute, Endocrinology Research Center Address: 117036, Moscow, Dmitriya Ul’yanova St., 11; tel: (499) 124-45-00

nephro@endocrincentr.ruKutyrinaI. M.КутыринаИ. М.
Russian Federation

PhD, Professor, Leading Research Worker, Department of Nephrology Research Center, I.M. Sechenov First Moscow State Medical University Address: 119992, Moscow, Rossolimo St., 11/4, tel.: (499) 248-41-66

nephro@endocrincentr.ruIl’inA. V.ИльинА. В.
Russian Federation

Head of the Laboratory of Clinical Biochemistry, Endocrinology Research Center Address: 117036, Moscow, Dmitriya Ul’yanova St., 11; tel: (499) 126-76-00

viktor.ilin2011@inbox.ruArbuzovaM. I.АрбузоваМ. И.
Russian Federation

PhD, Leading Research Worker, Laboratory of Clinical Biochemistry, Endocrinology Research Center Address: 117036, Moscow, Dmitriya Ul’yanova St., 11; tel: (499) 612-78-58

margarita.arbuzova2010@inbox.ruDedovI. I.ДедовИ. И.

RAS and RAMS academician, PhD, Professor, RAMS president, Director of Endocrinology Research Center Address: 117036, Moscow, Dmitriya Ul’yanova St., 11; tel: (499) 124-43-00

nephro@endocrincentr.ruScientific Centre of Endocrinology, Moscow, Russian FederationЭндокринологический научный центр, Москва, Российская ФедерацияI.M. Sechenov First Moscow State Medical University, Moscow, Russian FederationПервый Московский государственный медицинский университет им. И.М. Сеченова, Москва, Российская Федерация22022013682Vestnik Rossiiskoi akademii medetsinskikh nauk / Annals of the Russian academy of medical sciencesВестник Российской академии медицинских наук354207082015Copyright ©; 1970, "Paediatrician" Publishers LLCCopyright ©; 1970, Издательство "Педиатръ"1970"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/article/view/213

This original article contains the authors own data on homeostasis of angiogenic growth factors (vascular endothelial growth factor — VEGF, angiopoietin 1 and 2 — Ang-1, Ang-2) in diabetic kidney disease. The aims of study were evaluation of alteration on serum concentration of circulating VEGF, Ang-1 and Ang-2, and of their association with markers of renal damage (albuminuria, glomerular filtration rate) and anemia in patients with diabetes mellitus. We studied 78 patients type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Among this group 37 patients had chronic kidney disease. The serum level of VEGF was elevated in T1DM patients and was associated with degree of proteinuria. The serum concentration of Ang-2 was higher in patients with chronic kidney disease (T1DM and T2DM), renal failure (T1DM), proteinuria and anemia (T2DM). Ang-2 strongly associated with albuminuria (T1DM and T2DM), glomerular filtration rate (T1DM) and hemoglobin (T2DM). Obtained results demonstrate that levels of VEGF and Ang-2 (but not Ang-1) are raised in patients with diabetic kidney disease and associated with markers of renal damage and anemia. These data indicate the presence of the disturbance of angiogenic growth factors (VEGF, Ang-2) homeostasis and activity in diabetic patients with chronic kidney disease.

В статье приведены собственные данные авторов, касающиеся гомеостаза ангиогенных факторов роста (сосудистый эндотелиальный фактор роста — СЭФР, ангиопоэтин 1 и 2 — Анг-1 и Анг-2) при диабетическом поражении почек. Целью исследования была оценка изменения сывороточной концентрации циркулирующих СЭФР, Анг-1 и Анг-2 и их связи с маркерами почечного повреждения (альбуминурия, скорость клубочковой фильтрации) и анемией у больных сахарным диабетом с хронической болезнью почек. В исследование было включено 78 больных сахарным диабетом 1-го и 2-го типа (из них хроническая болезнь почек была диагностирована у 37 человек). Содержание СЭФР в сыворотке было повышено у больных сахарным диабетом 1-го типа с поражением почек и связано со степенью выраженности протеинурии. Уровень циркулирующего Анг-2 был выше при наличии хронического заболевания почек (сахарный диабет 1-го и 2-го типа), почечной недостаточности (сахарный диабет 1-го типа), протеинурии и анемии (сахарный диабет 2-го типа). Анг-2 тесно коррелировал с альбуминурией (сахарный диабет 1-го и 2-го типа), скоростью клубочковой фильтрации (сахарный диабет 1-го типа) и гемоглобином крови (сахарный диабет 2-го типа). Полученные данные свидетельствуют, что диабетическое поражение почек характеризуется повышением концентрации циркулирующих ангиогенных факторов в сыворотке СЭФР и Анг-2 (но не Анг-1), наличием их связи с маркерами повреждения почек и анемией, что говорит о нарушении их гомеостаза и активности при наличии хронических болезней почек у больных сахарным диабетом.

angiopoietinsdiabetes mellitusdiabetic kidney diseasevascular growth factorангиопоэтиныдиабетическое поражение почексахарный диабетсосудистый эндотелиальный фактор роста1. Dedov I.I., Shestakova M.V. Diabeticheskaya nefropatiya [Diabetic Nephropathy]. Moscow, Universum Pablishing, 2000. 239 p.2. Shestakova M.V., Dedov I.I. Sakharnyi diabet i khronicheskaya bolezn' pochek [Diabetes and Chronic Kidney Disease]. Moscow, MIA, 2009. 482 p.3. Flyvbjerg A., Grønbaek, Bak M., Nielsen B., Christiansen T., Hill C., Logan A., Ørskov H. Diabetic kidney disease: the role of growth factors. Nephrol. Dial. Transplant. 1998; 13: 1104–1107.4. Aiello L.P., Wong J.-S. Role of vascular endothelial growth factor in diabetic vascular complications. Kidney Int. 2000; 58 (Suppl. 77): 1427–1430.5. Khamaisi M., Scrijvers B.F., Vriese A.S.D., Raz I., Flyvbjerg A. The emerging role of VEGF in diabetic kidney disease. Nephrol. Dial. Transplant. 2003; 18: 1104–1107.6. Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am. J. Physiol. Cell. Physiol. 2001; 280: 1358–1366.7. Ferrara N., Gerber H.P., LeCouter J. The biology of VEGF and its receptors. Nat. Med. 2003; 9 (6): 669–676.8. Lim H.S., Blann A.D., Chong A.Y., Freestone B., Lip G.H. Plasma vascular endothelial growth factor, angiopietin-1, and angiopoietin-2 in diabetes. Diabetes Care. 2004; 27 (12): 2918–2924.9. Lim H.S., Lip G.Y.H., Blann A.D. Angiopoietin-1 and angiopoietin-2 in diabetes mellitus: relationship to VEGF, glycaemic control, endothelial damage/dysfunction and atherosclerosis. Atherosclerosis. 2005; 180 (1): 113–118.10. Yang Y.B., Chen Z.J., Liu F., Huang S.M. The expression and significance of the angiopoietin-1 in the kidney of diabetic rats. Sichuan Da Xue Xue Bao Yi Xue Ban. 2007; 38 (1): 93–96.11. Levey A.S., Bosch J.P., Lewis J.B., Greene T., Rogers N., Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann. Intern. Med. 1999; 130: 461–470.12. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. Am. J. Kidney Dis. 2002; 39 (Suppl. 1): 1–266.13. World health organization. Nutritional Anemia: Report of WHO Scientific Group 1968. World Health Organization. Geneva.14. National Kidney Foundation: K/DOQI clinical practice guidelines for the treatment of anemia of chronic kidney disease. Update 2000. Am. J. Kidney Dis. 2001; 37 (Suppl. 1): 182–238.15. Simon M., Gröne N.J., Jöhren H.J., Kullmer J., Plate K.H., Risau W., Fuchs E. Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney. Am. J. Physiol. 1995; 268: 240–250.16. Thomas S., Vanuystel J., Gruden G., Rodriguez V., Burt D., Gnudi L., Hartley B., Viberti G. Vascular endothelial growth factor receptors in human mesangium in vitro and glomerular disease. J. Am. Soc. Nephrol. 2000; 11: 1236–1243.17. Eremina V., Cui S., Gerber H., Ferrara N., Haigh J., Nagy A., Ema M., Rossant J., Jothy S., Miner J.H., Quaggin S.E. Vascular endothelial growth factor for a signaling in the podocyte-endothelial compartment is required for a mesangial cell migration and survival. J. Am. Soc. Nephrol. 2006; 17: 724–735.18. Cha D.R., Kim N.H., Yoon J.W., Jo S.K., Cho W.Y., Kim H.K., Won N.H. Role of vascular endothelial growth factor in diabetic nephropathy. Kidney Int. 2000; 58 (Suppl. 77): 104–112.19. Hovid P., Tarnow L., Oestergaard P.B., Parving H.-H. Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy. Kidney Int. 2000; 57 (Suppl. 75): 56–61.20. Cai J., Boulton M. The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye. 2002; 16: 242–260.21. Mohamed Q., Gillies M.C., Wong T.Y. Management of diabetic retinopathy. Syst. Review. JAMA. 2007; 298: 902–916.22. Unemori E.N., Ferrara N., Bauer F.A., Amento E.P. Vascular endothelial growth factor induces interstitial collagenases expression in human endothelial cells. J. Cell. Physiol. 1992; 153: 557–562.23. Nakagawa T., Kosugi T., Haneda M., Rivard C.J., Long D.A. Abnormal angiogenesis in diabetic nephropathy. Diabetes. 2009; 58: 1471–1478.24. Bortoloso E., Del Prete D., Vestra M.D., Gambaro G., saller A., Antonucci F., Baggio B., Anglani F., Fioretto P. Quantitave and qualitative changes in vascular endothelial growth factor gene expression in glomeruli of patients with type 2 diabetes. Eur. J. Endocrin. 2004; 150: 799–807.25. Ostendorf T., Kunter U., Eitner F. et al. VEGF165 mediates glomerular endothelial repair. J. Clin. Invest. 1999; 104 (7): 913–923.26. Masuda Y., Shimizu A., Mori T., Ishiwata T., Kitamura H., Ohashi R., Ishizaki M., Asano G., Sugisaki Y., Yamanaka N. Vascular endothial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis. Am. J. Pathol. 2001; 159: 599–608.27. Thomas M., Augustin H.G. The role of angiopoietins in vascular morphogenesis. Angiogenesis. 2009; 12: 125–137.28. Thurston G. Role angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphagenesis. Cell Tissue Res. 2003; 314: 61–68.29. Feldeman D.C., Blann A.D., Lip G.Y.H. Angiogenesis: basic pathophisiology and implication for disease. Eur. Heart J. 2003; 24: 586–603.30. Woolf A., Gnudi L., Long D.A. Roles of angiopoietins in kidney development and disease. J. Am. Soc. Nephrol. 2009; 20: 239–244.31. Suri C., Jones P.F., Patan S., Bartunkova S., Maisonpierre P.C., Davis S., Sato T.N., Yancopoulos G.D. Requisite role of angiopoietin-1, a ligand for the TIE-2 receptor, during embryonic angiogenesis. Cell. 1996; 87: 1171–1180.32. Pitera J.E., Woolf A.S., Gale N.W., Yancopoulos G.D., Yuan H.T. Dysmorphogenesis of kidney cortical peritubular capillaries in angiopoietin-2 deficient mice. Am. J. Pathol. 2004; 165: 1895–1906.33. Satchell S.C., Harper S.J., Tooke J.E., Kerjaschki D., Saleem M.A., Mathieson P.W. Human podocytes express angiopoietin-1, a potential regulator of glomerular vascular endothelial growth factor. J. Am. Soc. Nephrol. 2002; 13: 544–550.34. Kim I., Kim H.G., So J-N., Kim J.H., Kwak H.J., Koh G.Y. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Circ. Res. 2000; 86: 24–29.35. Thurston G., Rudge J.S., Ioffe E.,, Zhou H., Ross L., Croll S.D., Glazer N., Holash J., McDonald D.M., Yancopoulos G.D. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat. Med. 2000; 6: 460–463.36. Lee S., Kim W., Moon S.-O., Sung M.J., Kim D.K., Kang K.P., Jang K.Y., Lee S.Y., Park B.H., Koh G.Y., Park S.K. Renoprotective effect of COMP-angiopoietin-1 in db/db mice with type 2 diabetes. Nephrol. Dial. Transplant. 2007; 22: 396–408.37. Pfister F., Wang Y., Schreiter K., von Hagen F., Altvater K., Hoffmann S., Deutsch U., Hammes H-P., Feng Y. Retinal overexpression of angiopoietin-2 mimics diabetic retinopathy and enhances vascular damage in hyperglycemia. Acta Diabetol. 2010; 47: 59–64.38. Yuan H.T., Tipping P.G., Li X.Z., Long D.A., Woolf A.S. Angiopoietin correlates with glomerular capillary loss in anti-glomerular basement membrane glomerulonephritis. Kidney Int. 2002; 61: 2078–2089.39. Lu Y.H., Deng A.G., Li N., Song M.N., Yang X., Liu J.S. Changes in angiopoietin expression in glomeruli involved in glomerulosclerosis in rats with daunorubicin-induced nephrosis. Acta Pharmacol. Sin. 2006; 27: 579–587.40. Kümper P., Hellpap J., David S., Horn R., Leitolf H., Haller H., Haubitz M. Circulating angiopoietin-2 is a marker and potential mediator of endothelial cell detachment in ANCA-associated vasculitis with renal involvement. Nephrol. Dial. Transplant. 2009; 24: 1845–1850.41. Davis B., Cas A.D., Long D.A., White K.E., Hayward A., Ku C-H., Woolf A.S., Bilous R., Viberti G., Gnudi L. Podocyte-specific expression of angiopoietin-2 causes proteinuria and apoptosis of glomerular endothelia. J. Am. Soc. Nephrol. 2007; 18: 2320–2329.42. David S., Kümper P., Lukasz A., Fliser D., Martens-Lobenhoffer J., Bode-Böger S.M., Kliem V., Haller H., Kielstein J.T. Circulating angiopoietin-2 levels increase with progress of chronic kidney disease. Nephrol. Dial. Transplant. 2010; 25: 2571–2579.43. David S., Kümpers P., Hellpap J., Horn R., Leitolf H., Haller H., Kielstein T. Angiopoietin 2 and cardiovascular disease in dialysis and kidney transplantation. Am. J. Kidney Dis. 2009; 53: 770–778.44. Fiedler U., Scharpfenecker M., Koidl S. et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood. 2004; 103: 4150–4156.45. Singh H., Milner C.S., Aguilar Hernandez M.M., Nicholas N.P., Brindle P.J. Vascular endothelial growth factor activates the Tie family of receptor tyrosine kinases. Cell Signal. 2009; 21: 1346–1350.46. Parka Y.S., Kimb N.H., Joa I. Hypoxia and vascular endothelial growth factor acutely up-regulate angiopoietin-1 and Tie2 mRNA in bovine retinal pericytes. Microvasc. Res. 2003; 65: 125–131.47. Rizkalla B., Forbes J.M., Cao Z., Boner G., Cooper M.E. Temporal renal expression of angiogenic growth factors and their receptors in experimental diabetes: role of the renin-angiotensin system. J. Hypertens. 2005; 23: 153–164.48. Yamamoto Y., Maeshima Y., Kitayama H. Y., Kitamura S., Takazawa Y., Sugiyama H., Yamasaki Y., Makino H. Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes. 2004; 53: 1831–1840.49. Ichinose K., Maeshima Y., Yamamoto Y., Kitayama H., Takazawa Y., Hirokoshi K., Sugiyama H., Yamasaki Y., Eguchi K., Makino H. Anti-angiogenic endostatin peptide ameliorates renal alterations in the early stage of type 1 diabetic nephropathy model. Diabetes. 2005; 54: 2891–2903.50. Ichinose K., Maeshima Y., Yamamoto Y., Kinomura M., Hirokoshi K., Kitayama H., Takazawa Y., Sugiyama H., Yamasaki Y., Agata N., Makino H. 2-(8-hydroxy-6-methoxy-1-oxo-1h-2-benzopyran-3-yl) propionic acid, an inhibitor of angiogenesis, ameliorates renal alterations in obese type 2 diabetic mice. Diabetes. 2006; 55: 1232–1242.51. Mita A.C., Takimoto C.H., Mita M., Tolcher A., Sankhala K., Sarantopoulos J., Valdivieso M., Wood L., Rasmussen E., Sun Y-N., Zhong Z.D., Bass M.B., Le N, LoRusso P. Phase 1 Study of AMG 386, a selective angiopoietin ½-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors. Clin. Cancer Res. 2010; 16(11): 3044–3056.