POLYMORPHIC MARKER 4G/5G OF GENE PAI-1 IN CHILDREN WITH CHRONIC GLOMERULONEPHRITIS

THE AIM of the investigation was to determine polymorphism of gene PAI-1 linked with deletion/insertion of guanine in – 675 position from a starting point of the promoter in patients with CGN. PATIENTS AND METHODS. The polymorphic marker 4G/5G of gene PAI was investigated in 170 patients with chronic glomerulonephritis. The patients were divided into three groups by the data of morphological investigation. According to the morphological classification the first group included 86 children with nephrotic syndrome with minimal changes (NSMC), 29 patients of the second group had focal-segmental glomerulosclerosis (FSGS) and 55 patients of the third group had mesangioproliferative nephritis (MPN). RESULTS. A reliable association of the polymorphic marker 5G5G and allel 5G with NSMC and FSGC (χ2=9,85; p=0.002 and χ2=8.5; p= 0.004 respectively) and (χ2=10.53; p=0.001 and χ2=9.18; p= 0.0025 respectively). MPN is reliably associated with genotype 4G4G and allel 4G (χ2=5.1; p=0.024 and χ2=5.34; p= 0.02). The least renal survival was found in genotype 4G4G (p=0.055) carriers. CONCLUSION. The investigation fulfilled has demonstrated a difference between the associations of the polymorphic marker 4G/5G of gene PAI-1 in children with NSMC, FSGS and MPN. The results have shown the influence of allle 4G on the development of proliferative nephrites and progression of the disease.

chronic glomerulonephritis, nephrotic syndrome with minimal changes, focal-segmental glomerulosclerosis, mesangioproliferative glomerulonephritis, gene PAI-1

1. Ратнер МЯ, Серов ВВ, Томилина НА. Ренальные дисфункции.Медицина, М., 1977; 254

2. Тареева ИВ. Нефрология. Руководство для врачей. Медицина, М., 2000; 236-248

3. Чиж АС. Современные представления об этиологии и патогенезе диффузного гломерулонефрита. Здравоохр Белоруссии 1972; 4: 2-6

4. Шахмалова МШ, Шестакова МВ, Чугунова ЛА, Дедов ИИ. Вазоактивные факторы эндотелия сосудов у больных инсулин-независимых сахарным диабетом с поражением почек. Тер архив 1996; (6): 43-45

5. Feng L, Tang WW, Loskutoff DJ, Wilson CB. Dysfunction of glomerular fibrinolysis in experimental antiglomerular basement membrane antibody glomerulonephritis. J Am Soc Nephrol 1992; 3: 1753-1764

6. Besbas N, Erbay A, Saatci U et al. Trombomodulin, tissue plasminogen activator inhibitor-1 in Henoch-Scholein purpura. Clin Exp Rheumatol 1998; 16: 95-98

7. Allisone A. Eddy. Plasminogen activator inhibitor –1 and the kidney. Am J Physiol Renal Physiol 2002; 283: 209-220

8. Xu Y, Hagege J, Mougenot B et al. Different expression of the plasminogen activator system in renal trombotic microangiopathy and the normal human kidney. Kidney Int 1996; 50: 2011-2019

9. Duymelinck C, Dauwe SHE, De Greef KEJ et al. TIMP 1 gene expression and PAI_1 antigen after unilateral obstruction in the adult male rat. Kidney Int 2000; 58: 1186-1201

10. Duymelinck C, Dauwe SHE, De Greef KEJ et al. TIMP 1 gene expressionvand PAI_1 antigen after unilateral obstruction in the adult male rat. Kidney Int 2000; 58: 1186-1201

11. Guan L, Ji X, Wang J et al. Association of plasminogen activator inhibitor-1 gene 4G/5G polymorphism and coronary heart disease in Chinese patients. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2002;19: 393-396

12. Oda T, Jung YO, Kim H et al. PAI-1 deficiency attenuates the fibrinogenic response to ureteral obstruction. Kidney Int 2001; 30: 587-596

13. Brooun NJ, Nakamura S, Ma L et al. Aldesterone modulates plasminogen activator, inhibitor –1 and glomerulosclerosis in vivo. Kidney Int 2000; 58:1219-1227

14. Oikawa T, Freeman M, Lo W et al. Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibitor. Kidney Int 1997; 51: 164-172

15. Ma LJ, Nakamura S, Whitssitt JS et al. Regression of sclerosis in anging by an angiotensin inhibitor-iduced decrease in PAI-1. Kidney Int 2000; 58: 2425-2436

16. Tamaki K, Okuda S, Nakayama M et al. Transforming growth factor –beta 1 in hypertensive renal injury in Dahl salt-sensitive rats. J Am Soc Nephrol 1996; 7: 2578-2589

17. Eddy AA. Interstitial inflammation, and fibrosis in rats with diet-induced hypercholesterolemia. Kidney Int 1996; 50: 1139-1149

18. Keeton M, Eguchi Y, Sawadey M et al. Cellular localization of type 1 plasminogen activator inhibitor messenger RNA and protein in murine renal tissue.Am J Pathol 1993; 142: 59-70

19. Sugatani J, Igarashi T, Manucata M et al. Activator of coagulation in C57BL/6 mice given verotoxin 2 ( VT 2) and the effect of co-administration of LPS with VT 2. Tromb Res 2000; 100: 61-72

20. Haraguchi M, Border WA, Huang Y, Noble NA. t-PA promotes glomerular plasmin generation and matrix degradation in experimental glomerulonephritis. Kidney Int 2001; 59: 2146-2155

21. Shihab FS, Andoh TF, Tanner AM et al. Role of transforming growth factor-βin experimental chronic cyclosporine nephropathy. Kydney Int 1996; 49: 1141-1151

22. Sihab FS, Bennett WM, Tanner AM, Andoh TF. Mechanism of fibrosis in experimental tacrolimus nephrotoxicity. Transplantation 1997; 64: 1829-1837

23. Tomooka S, Border WA, Marshall BC, Noble NA. Glomerular matrix accumulation is linked to inhibition of the plasmin protease system. Kidney Int 1992; 42: 1462-1469

24. Hamano K, Iwano M, Akai Y et al. Expression of glomerular plasminogen activator inhibitor type 1 in glomerulonephritis. Am J KidneyDis 2002; 30: 695-705

25. Yamamoto T, Noble NA, Cohen AH et al. Expression of transforming growth factor βisoforms in human glomerular diseases. Kidney Int 1996; 49: 461-469

26. Yamaamoto T, Nakamura T, Noble NA et al. Expression of transforming growth factor βis elevated in human and experimental diabetic nephropathy. Proc Nath Acad Sci USA 1993; 90: 1814-1818

27. Stegnar M, Uhrin P, Peternel P et al. The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: relationship to plasma PAI-1 level in venous thromboembolism. Thromb Haemost 1998; 79: 975-979

28. Gilles P, Bosson JL, Golshayan D et al. The diamant alpin dialys cohort study: Clinico-biological characteristics and cardiovascular genetic risk profile of incendent patients. J Nephrol 2004; 17: 66-75

29. Grubic N, Stegnar M, Peternel P et al. A novel G/A and the 4G/5G polymorphism within the promoter of the plasminogen activator inhibitor-1 gene in patients with deep vein thrombosis. Thromb Res 1996;15:431-443

30. Gong R, Liu Z, Chen Z, Li L. Genetic variations in plasminogen activator inhibitor-1 gene and beta fibrinogen gene associated with glomerular microthrombosis in lupus nephritis and the gene dosage effect. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2002; 19: 1-5

31. Wang AY, Poon P, Lai FM et al. Plasminogen activator inhibitor –1 gene polymorphism 4G/4G genotype and lupus nephritis in Chinese patients. Kidney Int 2001; 59: 1520-1528

32. Suzuki H, Sakuma Y, Kanesaki Y. Close relationship of plasminogen activator inhiditor-1 4G/5G polymorphism and progression of Ig-A nephropathy. Clin Nephrol 2004; 62: 173-179

33. Приходина ЛС, Заклязьминская ЕВ, Полтавец НВ и др. Полиморфизм гена ингибитора активатора плазмино-гена-1 у детей с гормонорезистентным нефротическим синдромом.VI Cъезд науч.об-ва нефрологов. Сборник тезисов; 2005: 43

34. Margaglione M, Cappucci G, d’Addedda M et al. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis relation to environmental and genetic determinants. Arterioscler Thromb Vasc Biol 1998; 18:562-567

35. Tang WW, Feng L, Xia Y, Wilson CB. Extracellular matrix accumulation in immune-mediated tubulointerstitial injury. Kidney Int 2003; 45: 1077-1084