TGF-β_1 VEGF在儿童原发性肾病综合征中的表达及其临床意义研究
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摘要
目的： 研究转化生长因子β1（TGF－β1）和血管内皮生长因子（VEGF）与儿童原发性肾病综合征（PNS）蛋白尿的关系及其在不同病理类型肾组织中的表达差异，探讨PNS蛋白尿的发生机理及肾小球疾病肾组织纤维化的影响因素，指导治疗，判断预后。方法： 应用酶联免疫吸附双抗体夹心法（ELISA）测定正常对照组10例、NS组患儿28例的血清TGF－β1、VEGF水平，比较两指标血清水平变化与蛋白尿之间、与肾病不同病理类型之间的关系及两者的相关性；应用免疫组织化学S-P二步法检测12例不同病理类型NS肾组织及3例正常肾组织中TGF－β1、VEGF的蛋白表达情况，并比较其差异。结果： 1.蛋白尿阳性NS组，其血清TGF－β1、VEGF水平均分别较正常组和蛋白尿阴性NS组显著增高（P<0.05），且两指标之间呈正相关（r =0.4305）。 2. 在NS不同病理类型中，FSGS组血清TGF－β1水平较MCNS、MSPGN组及对照组显著升高(P<0.01)。 3. FSGS及MSPGN组血清VEGF水平较MCNS及对照组显著增高(P<0.01)。 4. TGF－β1、VEGF在NS组病变肾组织中阳性表达面积均显著高于对照组(P<0.01)。 5. TGF－β1的蛋白表达强度在MCNS、MSPGN、MN、 FSGS四组中呈逐渐增强趋势，尤其在伴间质纤维化组，TGF－β1表达较无纤维化组明显增强，其差异具有显著性（P<0.05）；而VEGF蛋白表达强度在NS不同病理类型之间以及有无间质纤维化之间差异无显著性(P>0.05)。 结论： 1. 血清TGF－β1、VEGF水平与NS蛋白
尿的产生有关，且与肾脏病理损害类型有关。 2. NS病人肾组织均存在TGF－β1、VEGF蛋白表达增强,尤以TGF－β1表达增强为著,且其表达强度与肾小管间质纤维化程度有关。3.抗VEGF和 TGF－β1的研究和应用可能是治疗NS蛋白尿及改善本病预后，防止肾纤维化的重要手段。
Objective To study the relationship of transforming growth factor beta 1 (TGF-β1) and vascular endothelial growth factor (VEGF) with proteinuria in children with primary nephrotic syndrome(PNS) and the expression discrepancy in varied pathology type by renal biopsy and to explore mechanism of the proteinuria and influence factors of fibrosis in PNS in order to guide the treatment and to judge the prognosis. Methods Twenty-eight patients were as test group, and ten healthy children were as control group. In test group 7 cases were in remission and others were divided into three groups which were confirmed by renal biopsy: minimal change nephrotic syndrome (MCNS) in 5 patients, mesangial proliferative glomerulonephritis (MSPGN) in 12 and focal segmental glomerulo- sclerosis (FSGS) in 4. The peripheral blood serum levels for the protein of TGF-β1 and VEGF were measured by enzyme-linked immunosorbent assay (ELISA), comparing the associated for their serum levels of protein with proteinuria and pathologic types. The protein expression of TGF-β1 and VEGF were analysed by immunohistochemistry staining with streptavidin-peroxidase in nephritic tissues of different pathologic types in twelve cases and control group in three . Results 1.The protein levels of TGF-β1, VEGF in blood serum were higher in the test group with proteinuria than remission (P<0.05), and there was positive relation between the two index（r =0.4305）.2. The protein levels of TGF-β1 in blood serum was much higher in FSGS than MCNS, MSPGN and control (P<0.01). 3. The protein levels of VEGF in blood serum was much higher in FSGS and MSPGN than MCNS and control group (P<0.01). 4. The expression for positive area of TGF-β1 and VEGF were much higher in nephritic tissues with NS than that with
control group(P<0.01). 5. The expression for positive intensity of TGF-β1 protein was higher and higher in different nephritic tissues from MCNS, MSPGN, MN to FSGS, especially the increasing expression of TGF-β1 which was associated with fibrosis degree of tubule and interstitial, and there were statistical significance (P<0.01). But the expression for positive intensity of VEGF protein was no statistical significance in all test groups include interstitial fibrosis (P>0.05). Conclusions 1. Serum levels of TGF-β1 and VEGF were associated with proteinuria and different types of pathology in children with primary nephrotic syndrome. 2. Positive expression intensity of TGF-β1 and VEGF in nephritic tissues was higher in PNS than in control group, especially the increasing expression of TGF-β1 which was associated with fibrosis degree of tubule and interstitial in PNS. 3. Anti-VEGF and Anti- TGF-β1 may be a important means in treating proteinuria, improving the prognosis and preventing the fibrosis in PNS.
尿的产生有关，且与肾脏病理损害类型有关。 2. NS病人肾组织均存在TGF－β1、VEGF蛋白表达增强,尤以TGF－β1表达增强为著,且其表达强度与肾小管间质纤维化程度有关。3.抗VEGF和 TGF－β1的研究和应用可能是治疗NS蛋白尿及改善本病预后，防止肾纤维化的重要手段。
Objective To study the relationship of transforming growth factor beta 1 (TGF-β1) and vascular endothelial growth factor (VEGF) with proteinuria in children with primary nephrotic syndrome(PNS) and the expression discrepancy in varied pathology type by renal biopsy and to explore mechanism of the proteinuria and influence factors of fibrosis in PNS in order to guide the treatment and to judge the prognosis. Methods Twenty-eight patients were as test group, and ten healthy children were as control group. In test group 7 cases were in remission and others were divided into three groups which were confirmed by renal biopsy: minimal change nephrotic syndrome (MCNS) in 5 patients, mesangial proliferative glomerulonephritis (MSPGN) in 12 and focal segmental glomerulo- sclerosis (FSGS) in 4. The peripheral blood serum levels for the protein of TGF-β1 and VEGF were measured by enzyme-linked immunosorbent assay (ELISA), comparing the associated for their serum levels of protein with proteinuria and pathologic types. The protein expression of TGF-β1 and VEGF were analysed by immunohistochemistry staining with streptavidin-peroxidase in nephritic tissues of different pathologic types in twelve cases and control group in three . Results 1.The protein levels of TGF-β1, VEGF in blood serum were higher in the test group with proteinuria than remission (P<0.05), and there was positive relation between the two index（r =0.4305）.2. The protein levels of TGF-β1 in blood serum was much higher in FSGS than MCNS, MSPGN and control (P<0.01). 3. The protein levels of VEGF in blood serum was much higher in FSGS and MSPGN than MCNS and control group (P<0.01). 4. The expression for positive area of TGF-β1 and VEGF were much higher in nephritic tissues with NS than that with
control group(P<0.01). 5. The expression for positive intensity of TGF-β1 protein was higher and higher in different nephritic tissues from MCNS, MSPGN, MN to FSGS, especially the increasing expression of TGF-β1 which was associated with fibrosis degree of tubule and interstitial, and there were statistical significance (P<0.01). But the expression for positive intensity of VEGF protein was no statistical significance in all test groups include interstitial fibrosis (P>0.05). Conclusions 1. Serum levels of TGF-β1 and VEGF were associated with proteinuria and different types of pathology in children with primary nephrotic syndrome. 2. Positive expression intensity of TGF-β1 and VEGF in nephritic tissues was higher in PNS than in control group, especially the increasing expression of TGF-β1 which was associated with fibrosis degree of tubule and interstitial in PNS. 3. Anti-VEGF and Anti- TGF-β1 may be a important means in treating proteinuria, improving the prognosis and preventing the fibrosis in PNS.
引文
Yan K, Nakahara K, Awa S, et al. The increase of memory T cell subsets in children with idiopathic nephritic syndrome.[J]. Nephron, 1998,79(3):274-278.
Shulman K, Rosen S, Tognazzi K, et al. Expression of vascular permeability factor(VPF/VEGF) is altered in many glomerular diseases. J Am Soc Nephrol 1996;7:661-6
Matsumoto K, Kanmatsuse K. Transforming growth factor-betal inhibits vascular permeability release by Tcells in normal subjects and in patients with minimal change nephritic syndrome.[J]. Nephron, 2001 Feb; 87(2):111-7
中华医学会儿科学分会肾脏病学组。小儿肾小球疾病的临床分类、诊断及治疗。中华儿科杂志，2001，39：746-749.
诸福棠主编.实用儿科学(第七版).北京：人民卫生出版社，2002：1628-1630.
Daniel V, Trautmann Y, Konrad M, et al. T-lymphocyte populations, cytokines and other growth factors in serum and urine of children with idiopathic nephrotic syndrome.[J]. Clin Nephrol, 1997,47(5):289-297.
Frank C, Herrmann M, Fernandez S, et al. Dominant T cells in idiopathic nephrotic syndrome of childhood.[J]. Kidney Int, 2000, 57(2):510-517.
Neuhaus TJ, Shah V, Callard RE,et al. T-lymphocyte activation in steroid-sensitive nephritic syndrome in childhood.[J]. Nephrol Dial Transplant, 1995, 10(8):1348-1352.
Stachowski J, Barth C, Michalkiewicz J, et al. Th1/Th2 balance and CD45-positive T cell subsets in primary nephritic syndrome.[J]. Pediatr Nephrol, 2000,14(8-9):779-785.
Horita Y, Miyazaki M, Koji T, Kobayashi N, Shinbuya M, Razzaque MS, Cheng M, Ozono Y, Kohno S, Taguchi T. Expresion of VEGF and its receptors in rat with protein-overload nephrosis. Nephrol Dial Transplant 1998; 13:2519-28.
Webb NJA, Watson CJ, Roberts ISD, Bottomly MJ, Jones CA, Lewis MA, Postlethwatte RJ. Circulating vascular endothelial growth factor is not increased during relapses of steroid-sensitive nephritic syndrome. [J]. Kidney Int 1999 ; 55: 1063-71.
Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature, 1996,380:435.
Bussolino F, Mantovani A, Persico G . Molecular mechanisms of blood vessel formation. TIBS, 1997, 22:251.
Guba M., von Breitenbuch P., Steinbauer M. i wsp.: Rapamycin inhibits primary and metastatic tumor growth by antiangiogensis: involvement of vascular endothelial growth factor. Nature. Med., 2002; 8: 128-135
Brown LF, Detmar M, Claffey K, et al. Vascular permeability factar/vascular endothelial growth factor: A multifunctional angiogenic cytokine. Exs, 1997, 79:233.
Watanabe Y, Lee SW, Detmar M, et al.Vascular permeability factor/ vascular endothelial growth factor (vpf/vegf) delays and induces escape from senescence in human dermal microvascular endothelial cells. Oncogene,1997, 14:2025.
Cao Y, Ji WR, Qi P, et al. Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing. Biochem Biophys Res Commun, 1997, 235(3):493.
Cao Y, Chen H, Zhou L, et al. Heterodimers of placenta growth factor/ vascular endothelial growth factor. [J] Biol Chem, 1996, 271(6):3154.
Cheong HI, Lee JH, Hahn H, Park HW, Ha IS, Choi Y. Circulating VEGF and TGF-beta1 in children with idiopathic nephritic syndrome. [J] Nephrol. 2001 Jul-Aug; 14(4):263-9.
Lijima K, Yoshikawa N, Connolly DT, Nakamura H. Expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) by meseangial cells. (abst) [J] Am Soc Nephrol 1992; 3:514.
Kretzler M, Schroppel B, Merkle M, et al. Detection of meltiple vascular endothelial growth factor splice isoforms in single blomerular podocytes. [J] Kidney Int Suppl, 1998, 67:159-161.
Rosenkranz S, Flesch M, Amann K, et al. Alterations of beta-a-drenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-beta1. Am J Physiol Heart Circ Physiol, 2002,283: H1253-H1262.
Sharma K,Ziyaadeh FN.Perspectives in diabetes hyperglycemia and diabetic kidney disease:The case for trasforming growth factor-β as a key mediator [J].Diabetes,1995,44:1139.
Ziyadeh FN, Han DC. Involvement of transforming growth factor-b and its receptors in the pathogenesis of diabetic nephropathy [J]. Kidney Int, 1997, 52:87.
Akagi Y, Isaka Y, Arai M, et al. Inhibition of TGF-beta 1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glomerulonephritis. [J]. Kidney Int 1996;50:148-155.
Matsumoto K, Kanmatsuse K. Transforming growth factor-betal inhibits vascular permeability factor release by T cells in normal subjects and in patients with minimal-change nephritic syndrome. [J]. Nephron 2001 Feb; 87(2):111-117
Aoyama I, Miyazaki T, Takayama F, et al. Oral adsorbent ameliorates renal TGF-beta 1 expression in hypercholesterolemic rats. [J]. Kidney Int Suppl. 1999 Jul;71:S193-197
28.De Jong Js,Van Diest PJ. Van der Valk Pa, et al.Expression of growth factors,growth inhibiting factors, and their receptors in invasive breast cancer I: An inventory in search of autocrine and paracrine loops. [J] Pathol 1998 Jan; 184(1):44-52.
29.Saito H, Tsujitani S, I Keguchi M, et al. Relationship between the expression of Vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. [J] Cancer 1998; 78:1573-7.
Yokoyama H, Deckert T. Central role of TGF-β in the pathogenesis of diabetic nephropathy and macrovascular complieations:A hypothesis [J].Diabetic
Med,1996,13:313.
Strutz F,Müller GA.The role of tubuliointerstitial processes inprogression of primaary renal diseases. [J] Nephrol Dial Transplant,1994,9(Suppl)10～20.
Alexopoulos E, Stangou M, Papagianni A, et al. Factors influencing the
course and the response to treatment primary focal segmental glomerulosclerosis. [J]. Nephrol Dial Transplant. 2000
Sep;15(9):1348-1356.
Fujigaki Y, Watanable T, Ikegaya type I, II and III. Immunoelectron microscopic study on TGF-beta. [J]. Nephrol Dial Transplant. 2000 Feb;15(2):191-9.
Machy K, Striker L, Stauffer JW, et al. Transforming growth factor-β: murine glomerular receptors and responses of isolated glomerular cells. [J] Clin Invest, 1989, 83: 160-164.
35. Kopp JB, Factor VM, Mozes M, et al. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. [J]. Lab Invest 1996 Jun;74(6):991-1003
36. Alvarez RJ, Sun MJ, Haverty TP, et al. Biosynthetic and proliferative characteristics of tubulointerstitial fibroblasts probed with paracrine cytokines. [J] Kidney Int, 1992,41:14-23
37. Murakami K, Takemura T, Hino S, et al. Urinary transforming growth factor-beta in patients with glomerular diseases. [J]. Pediatr Nephrol 1997 Jun;11(3):334-336.
38.Border WA, Okuda S, Sporn MB, et al. Suppression of experimental glomerulonephritis by antiserum against TGF-β1. Nature, 1990, 46:371-376.
39.Eddy AA. Protein restriction reduces transforming growth factor-beta and interstitial fibrosis in nephrotic syndrome. Am J Physiol 1994 Jun; 266(6 Pt 2):F884-93.
40.E. Honkanen, A. M. Teppo, T. T?rnroth, P. H. Groop and C. Gr?nhagen-Riska. Urinary transforming growth factor-beta1 in membranous glomerulonephritis. [J]. Nephrol Dial Transplant 1997 (12):2562-2568.
41. Fan JM, Nig YY, Hill PA, et al. Transforming growth factory beta regulates tubular
epitheliar-myofibroblast transdifferentiation in vitro.[J].Kidney Int. 1999 Oct, 56(4):1455-1459.
42.Isaka Y, Tsujie M, Ando Y, et al. Transforming growth factor-beta 1 antisense oligodeoxynucleotides block interstitial fibrosis in unilateral obstruction. [J].Kidney Int. 2000,58;1885-1892.
43. Hartner A, Hilgers KF, Bitzer M, Veelken R, Schocklmann HO. Dynamic expression patterns of transforming growth factor-beta(2) and transforming growth factor-beta receptors in experimental glomerulonephritis. [J] Mol Med. 2003 Jan; 81(1):1-3.
44. ZHOU A , Ueno H, Shimomura M, Tanaka R, et al Blockade of TGF-beta action ameliorates renal dysfunction and histologic progression in anti-GBM nephritis. [J]. Kidney Int 2003;64:92-101.
45. Nicholas J.A. Webb, Carolyn J.et, al. Circulating vascular endothelial growth factor is not increased during relapses of steroid-sensitive nephrotic syndrome. [J]. Kidney International, 1999; 55:1063-1071.
46. E Bailey, M J Bottomley, S Westwell, J H Pringle, P N Furness, J Feehally. Vascular endothelial growth factor mRNA expression in minimal change, membranous, and diabetic nephropathy demonstrated by non-isotopic in situ hybridisation. [J]. Clin Pathol 1999;52:735-738
47. Seko Y, Nishimura H, Takahashi N, Ashida T, Nagai R. Serum levels of vascular endothelial growth factor and transforming growth factor-beta1 in patients with atrial fibrillation undergoing defibrillation therapy. Jpn Heart [J]. 2000 Jan;41(1):27-32
Carlos Guijaro, Jesus Egido. Transcription factor-κB and renal disease. [J].
Kidney Int, 2000,59: 415-424.
R. E. Gilbert, A. Akdeniz, S. Weitz, W. R. Usinger, C. Molineaux, S. E. Jones, R.
G. Langham, and G. Jerums. Urinary connective tissue growth factor excretion in patients with type 1 diabetes and nephropathy. [J]. Diabetes Care, September?1,?2003; 26(9): 2632 – 2636.
Shulman K, Rosen S, Tognazzi K, et al. Expression of vascular permeability factor(VPF/VEGF) is altered in many glomerular diseases. J Am Soc Nephrol 1996;7:661-6
Matsumoto K, Kanmatsuse K. Transforming growth factor-betal inhibits vascular permeability release by Tcells in normal subjects and in patients with minimal change nephritic syndrome.[J]. Nephron, 2001 Feb; 87(2):111-7
中华医学会儿科学分会肾脏病学组。小儿肾小球疾病的临床分类、诊断及治疗。中华儿科杂志，2001，39：746-749.
诸福棠主编.实用儿科学(第七版).北京：人民卫生出版社，2002：1628-1630.
Daniel V, Trautmann Y, Konrad M, et al. T-lymphocyte populations, cytokines and other growth factors in serum and urine of children with idiopathic nephrotic syndrome.[J]. Clin Nephrol, 1997,47(5):289-297.
Frank C, Herrmann M, Fernandez S, et al. Dominant T cells in idiopathic nephrotic syndrome of childhood.[J]. Kidney Int, 2000, 57(2):510-517.
Neuhaus TJ, Shah V, Callard RE,et al. T-lymphocyte activation in steroid-sensitive nephritic syndrome in childhood.[J]. Nephrol Dial Transplant, 1995, 10(8):1348-1352.
Stachowski J, Barth C, Michalkiewicz J, et al. Th1/Th2 balance and CD45-positive T cell subsets in primary nephritic syndrome.[J]. Pediatr Nephrol, 2000,14(8-9):779-785.
Horita Y, Miyazaki M, Koji T, Kobayashi N, Shinbuya M, Razzaque MS, Cheng M, Ozono Y, Kohno S, Taguchi T. Expresion of VEGF and its receptors in rat with protein-overload nephrosis. Nephrol Dial Transplant 1998; 13:2519-28.
Webb NJA, Watson CJ, Roberts ISD, Bottomly MJ, Jones CA, Lewis MA, Postlethwatte RJ. Circulating vascular endothelial growth factor is not increased during relapses of steroid-sensitive nephritic syndrome. [J]. Kidney Int 1999 ; 55: 1063-71.
Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature, 1996,380:435.
Bussolino F, Mantovani A, Persico G . Molecular mechanisms of blood vessel formation. TIBS, 1997, 22:251.
Guba M., von Breitenbuch P., Steinbauer M. i wsp.: Rapamycin inhibits primary and metastatic tumor growth by antiangiogensis: involvement of vascular endothelial growth factor. Nature. Med., 2002; 8: 128-135
Brown LF, Detmar M, Claffey K, et al. Vascular permeability factar/vascular endothelial growth factor: A multifunctional angiogenic cytokine. Exs, 1997, 79:233.
Watanabe Y, Lee SW, Detmar M, et al.Vascular permeability factor/ vascular endothelial growth factor (vpf/vegf) delays and induces escape from senescence in human dermal microvascular endothelial cells. Oncogene,1997, 14:2025.
Cao Y, Ji WR, Qi P, et al. Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing. Biochem Biophys Res Commun, 1997, 235(3):493.
Cao Y, Chen H, Zhou L, et al. Heterodimers of placenta growth factor/ vascular endothelial growth factor. [J] Biol Chem, 1996, 271(6):3154.
Cheong HI, Lee JH, Hahn H, Park HW, Ha IS, Choi Y. Circulating VEGF and TGF-beta1 in children with idiopathic nephritic syndrome. [J] Nephrol. 2001 Jul-Aug; 14(4):263-9.
Lijima K, Yoshikawa N, Connolly DT, Nakamura H. Expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) by meseangial cells. (abst) [J] Am Soc Nephrol 1992; 3:514.
Kretzler M, Schroppel B, Merkle M, et al. Detection of meltiple vascular endothelial growth factor splice isoforms in single blomerular podocytes. [J] Kidney Int Suppl, 1998, 67:159-161.
Rosenkranz S, Flesch M, Amann K, et al. Alterations of beta-a-drenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-beta1. Am J Physiol Heart Circ Physiol, 2002,283: H1253-H1262.
Sharma K,Ziyaadeh FN.Perspectives in diabetes hyperglycemia and diabetic kidney disease:The case for trasforming growth factor-β as a key mediator [J].Diabetes,1995,44:1139.
Ziyadeh FN, Han DC. Involvement of transforming growth factor-b and its receptors in the pathogenesis of diabetic nephropathy [J]. Kidney Int, 1997, 52:87.
Akagi Y, Isaka Y, Arai M, et al. Inhibition of TGF-beta 1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glomerulonephritis. [J]. Kidney Int 1996;50:148-155.
Matsumoto K, Kanmatsuse K. Transforming growth factor-betal inhibits vascular permeability factor release by T cells in normal subjects and in patients with minimal-change nephritic syndrome. [J]. Nephron 2001 Feb; 87(2):111-117
Aoyama I, Miyazaki T, Takayama F, et al. Oral adsorbent ameliorates renal TGF-beta 1 expression in hypercholesterolemic rats. [J]. Kidney Int Suppl. 1999 Jul;71:S193-197
28.De Jong Js,Van Diest PJ. Van der Valk Pa, et al.Expression of growth factors,growth inhibiting factors, and their receptors in invasive breast cancer I: An inventory in search of autocrine and paracrine loops. [J] Pathol 1998 Jan; 184(1):44-52.
29.Saito H, Tsujitani S, I Keguchi M, et al. Relationship between the expression of Vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. [J] Cancer 1998; 78:1573-7.
Yokoyama H, Deckert T. Central role of TGF-β in the pathogenesis of diabetic nephropathy and macrovascular complieations:A hypothesis [J].Diabetic
Med,1996,13:313.
Strutz F,Müller GA.The role of tubuliointerstitial processes inprogression of primaary renal diseases. [J] Nephrol Dial Transplant,1994,9(Suppl)10～20.
Alexopoulos E, Stangou M, Papagianni A, et al. Factors influencing the
course and the response to treatment primary focal segmental glomerulosclerosis. [J]. Nephrol Dial Transplant. 2000
Sep;15(9):1348-1356.
Fujigaki Y, Watanable T, Ikegaya type I, II and III. Immunoelectron microscopic study on TGF-beta. [J]. Nephrol Dial Transplant. 2000 Feb;15(2):191-9.
Machy K, Striker L, Stauffer JW, et al. Transforming growth factor-β: murine glomerular receptors and responses of isolated glomerular cells. [J] Clin Invest, 1989, 83: 160-164.
35. Kopp JB, Factor VM, Mozes M, et al. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. [J]. Lab Invest 1996 Jun;74(6):991-1003
36. Alvarez RJ, Sun MJ, Haverty TP, et al. Biosynthetic and proliferative characteristics of tubulointerstitial fibroblasts probed with paracrine cytokines. [J] Kidney Int, 1992,41:14-23
37. Murakami K, Takemura T, Hino S, et al. Urinary transforming growth factor-beta in patients with glomerular diseases. [J]. Pediatr Nephrol 1997 Jun;11(3):334-336.
38.Border WA, Okuda S, Sporn MB, et al. Suppression of experimental glomerulonephritis by antiserum against TGF-β1. Nature, 1990, 46:371-376.
39.Eddy AA. Protein restriction reduces transforming growth factor-beta and interstitial fibrosis in nephrotic syndrome. Am J Physiol 1994 Jun; 266(6 Pt 2):F884-93.
40.E. Honkanen, A. M. Teppo, T. T?rnroth, P. H. Groop and C. Gr?nhagen-Riska. Urinary transforming growth factor-beta1 in membranous glomerulonephritis. [J]. Nephrol Dial Transplant 1997 (12):2562-2568.
41. Fan JM, Nig YY, Hill PA, et al. Transforming growth factory beta regulates tubular
epitheliar-myofibroblast transdifferentiation in vitro.[J].Kidney Int. 1999 Oct, 56(4):1455-1459.
42.Isaka Y, Tsujie M, Ando Y, et al. Transforming growth factor-beta 1 antisense oligodeoxynucleotides block interstitial fibrosis in unilateral obstruction. [J].Kidney Int. 2000,58;1885-1892.
43. Hartner A, Hilgers KF, Bitzer M, Veelken R, Schocklmann HO. Dynamic expression patterns of transforming growth factor-beta(2) and transforming growth factor-beta receptors in experimental glomerulonephritis. [J] Mol Med. 2003 Jan; 81(1):1-3.
44. ZHOU A , Ueno H, Shimomura M, Tanaka R, et al Blockade of TGF-beta action ameliorates renal dysfunction and histologic progression in anti-GBM nephritis. [J]. Kidney Int 2003;64:92-101.
45. Nicholas J.A. Webb, Carolyn J.et, al. Circulating vascular endothelial growth factor is not increased during relapses of steroid-sensitive nephrotic syndrome. [J]. Kidney International, 1999; 55:1063-1071.
46. E Bailey, M J Bottomley, S Westwell, J H Pringle, P N Furness, J Feehally. Vascular endothelial growth factor mRNA expression in minimal change, membranous, and diabetic nephropathy demonstrated by non-isotopic in situ hybridisation. [J]. Clin Pathol 1999;52:735-738
47. Seko Y, Nishimura H, Takahashi N, Ashida T, Nagai R. Serum levels of vascular endothelial growth factor and transforming growth factor-beta1 in patients with atrial fibrillation undergoing defibrillation therapy. Jpn Heart [J]. 2000 Jan;41(1):27-32
Carlos Guijaro, Jesus Egido. Transcription factor-κB and renal disease. [J].
Kidney Int, 2000,59: 415-424.
R. E. Gilbert, A. Akdeniz, S. Weitz, W. R. Usinger, C. Molineaux, S. E. Jones, R.
G. Langham, and G. Jerums. Urinary connective tissue growth factor excretion in patients with type 1 diabetes and nephropathy. [J]. Diabetes Care, September?1,?2003; 26(9): 2632 – 2636.