尿MCP-1在小儿原发性肾病综合征糖皮质激素治疗中的相关研究
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摘要
目的:原发性肾病综合征(idiopathic nephritic syndrome,INS)目前仍以糖皮质激素治疗为主,疗程长,副作用大。通过检测尿液中单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)、β-N-乙酰氨基葡萄糖苷酶(NAG)、Ⅳ型胶原(Ⅳ-Collager,Ⅳ-C)、24小时尿蛋白(24hUPRO)及血红细胞表面CD59、血清补体C3、C4在INS患儿糖皮质激素治疗不同阶段的水平变化及相关性,并结合部分肾组织活检病例,探讨尿MCP-1在指导INS患儿治疗和评估预后中的作用及与肾脏病理的关系。
方法:根据INS诊断标准,选择INS患儿38例。(1)初治患儿30例,根据患儿糖皮质激素8周治疗反应,包括激素敏感型INS(SSINS)15例、激素耐药型INS(SRINS)15例。(2)行肾组织活检8例,其中微小病变2例,局灶节段硬化3例,系膜增生2例,新月体(Ⅴ级)1例。同期选择健康儿童15例作为正常对照,各组间年龄、性别等组成无显著差异。初治患儿于治疗前2周内未服用过糖皮质激素类药物,各组患儿采样前无感染征象或感染已被控制,无心、脑、肝及血液系统疾病。应用双抗体夹心酶联免疫吸附试验、液相平衡竞争放射免疫分析法、化学法、流式细胞术等方法检测尿MCP-1、Ⅳ-C、NAG、血红细胞表面CD59及相关指标。SSINS组别于糖分皮质激素治疗前、治疗后4-8周、治疗3
Objective: Steroid-treatment is preferred for children with idiopathic nephritic syndrome (INS) at present, but it also brings many side effects for long-term treatment. By measuring the levels and correlations of urinary monocyte chemoattractant protein-1(MCP-1),Ⅳ-Collager (Ⅳ-C ) , N-acetyl-β-D-glucosaminidase(NAG), 24h urinary protein excretion, blood CD59 of red cellular surface and serum C3,C4 on the differently steroid-treated time of children with INS ,we study clinical values of measuring the level of MCP-1 in the urine of children with INS to guide steroid-treatment and to estimate prognosis, also to further investigate the underlying relationship between MCP-1 and the renal pathology of children with INS by several cases with a biopsy-proven diagnosis.
Methods: According to the diagnostic criterion of INS there were totally 38 children with INS who had be tested. 30 newly diagnosed patients, on the base of the 8 weeks steroid-treated responses they were divided two groups: steroid-sensitive INS (SSINS)(15 patients) and steroid-resistant (SRINS)(15 patients). Additional 8 patients with a biopsy-proven diagnosis, including minimal change glomerulonephritis(2 patients), focal segmental
方法:根据INS诊断标准,选择INS患儿38例。(1)初治患儿30例,根据患儿糖皮质激素8周治疗反应,包括激素敏感型INS(SSINS)15例、激素耐药型INS(SRINS)15例。(2)行肾组织活检8例,其中微小病变2例,局灶节段硬化3例,系膜增生2例,新月体(Ⅴ级)1例。同期选择健康儿童15例作为正常对照,各组间年龄、性别等组成无显著差异。初治患儿于治疗前2周内未服用过糖皮质激素类药物,各组患儿采样前无感染征象或感染已被控制,无心、脑、肝及血液系统疾病。应用双抗体夹心酶联免疫吸附试验、液相平衡竞争放射免疫分析法、化学法、流式细胞术等方法检测尿MCP-1、Ⅳ-C、NAG、血红细胞表面CD59及相关指标。SSINS组别于糖分皮质激素治疗前、治疗后4-8周、治疗3
Objective: Steroid-treatment is preferred for children with idiopathic nephritic syndrome (INS) at present, but it also brings many side effects for long-term treatment. By measuring the levels and correlations of urinary monocyte chemoattractant protein-1(MCP-1),Ⅳ-Collager (Ⅳ-C ) , N-acetyl-β-D-glucosaminidase(NAG), 24h urinary protein excretion, blood CD59 of red cellular surface and serum C3,C4 on the differently steroid-treated time of children with INS ,we study clinical values of measuring the level of MCP-1 in the urine of children with INS to guide steroid-treatment and to estimate prognosis, also to further investigate the underlying relationship between MCP-1 and the renal pathology of children with INS by several cases with a biopsy-proven diagnosis.
Methods: According to the diagnostic criterion of INS there were totally 38 children with INS who had be tested. 30 newly diagnosed patients, on the base of the 8 weeks steroid-treated responses they were divided two groups: steroid-sensitive INS (SSINS)(15 patients) and steroid-resistant (SRINS)(15 patients). Additional 8 patients with a biopsy-proven diagnosis, including minimal change glomerulonephritis(2 patients), focal segmental
引文
1 Prodjosudjadi W, Gerritsma JS, van Es LA, et al. Monocyte chemoattractant protein-1 in normal and diseased human kidneys: an immunohistochemical analysis. Clin Nephrol, 1995, 44(3):148~155
2 Rovin BH, Doe N, Tan LC. Monocyte chemoattractant protein-1 levels in patients with glomerular disease. Am J Kidney Dis, 1996, 27(5):640~646
3 胡亚美, 姜载芳主编.《诸福堂实用儿科》第 7 版,人民卫生出版社,2003,1627~1628
4 Sahali D, Pawlak A, le gouvello S, et al. Transcriptional and post transcriptional alterations of IkappaBalpha in active minimal change nephritic syndrome. J Am Soc Nephrol, 2001,12(8):1648~1658
5 Cao C, Lu S, Dong C, et al. Abnormal DNA-bingding of transcription factors in minimal change nephritic syndrome. Pediatr nephrol, 2001, 16(10):790~795
6 Nelson PJ, Krensky AM. Chemokines, lymphocyte sandviruses: What goes around, comes around. Curr Opin Immunol, 1998, 10(3):265~270
7 丁涵露, 朱妙珍. MCP-1 在肾小球肾炎中的表达及其意义.第三军医大学学报, 2000, 22(1):60~63
8 Sakai N, Wada T, Furuichi K, et al. The role of monocytechemotactic and activating factor (MCAF)/monocyte chemoattractant protein (MCP)-1 in subgroups of rapidly progressive glomerulonephritis. Nippon Jinzo Gakkai Shi, 1999, 41(7):704~711
9 Haberstroh U, Pocock J, Gomez-Guerrero C, et al. Expression of the chemokines MCP-1/CCL2 and RANTES/CCL5 is differentially regulated by infiltrating inflammatory cells. Kidney Int, 2002,62(4):1264~1276
10 Prodjosudjadi W, Gerritsma JS, Klar-Mohamad N, et al. Production and cytokine-mediated regulation of monocyte chemoattractant protein-1 by human proximal tubular epithelial cells. Kidney Int, 1995, 48(5):1477~1486
11 Schwarz M, Wahl M, Resch K, et al . IFN gamma induces functional chemokine receptor expression in human mesangial cells. Clin Exp Immunol, 2002, 128(2):285~294
12 Rovin BH, Lu L, Marsh CB. Lymphocytes induce monocyte chemoattractant protein-1 production by renal cells after Fc gamma receptor cross-linking: role of IL-1beta. J Leukoc Biol, 2001, 69(3):435~439
13 Heck S, Bender K, Kullmann Metal. Kbalpha- independent down regulation of NF-κB activity by glucocorticoids receptor. EMBOJ, 1997, 16(5):4698~4707
14 Schwarz M, Radeke H, Resch K, et al. Lymphocyte-derived cytokines induce sequential expression of monocyte-and Tcell-specific chemokines in human mesangial cells. KidneyInt, 1997, 52(6):1521~1531
15 Widmer U, Manogue KR, Cerami A, et al. Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-1A, and MIP-1B, members of the chemokine superfamily of proinflammatory cytokines. J Immunol, 1993, 150(11):4996~5012
16 de Haij S, Woltman AM, Bakker AC, et al.Production of inflammatory mediators by renal epithelial cells is insensitive to glucocorticoids. Br J Pharmacol, 2002, 137(2):197~204
17 Fede C, Conti G, Chimenz R, et al. N-acetyl-β-D-glucosaminidase and beta2-microglobulin: prognostic markers in idiopathic nephritic syndrome. J Nephrol, 1999, 12(1):51~55
18 Schneider A, Panzer U, Zahner G, et al. MCP-1 mediates collagen deposition in experimental glmerulonephritis by transforming growth factor-beta. Kidney Int, 1999, 56(1):135~144
19 Panzer U, Thaiss F, Zahner G, et al. Monocyte chemoattractant protein-1 and osteopontin differentially regulate monocytes recruitment in experimental glomerulonephritis. Kidney Int, 2001, 59(5):1762-1769
20 程叙扬,李晓玫,唐嘉薇等.微小病变患者尿蛋白对肾小管上皮细胞的损伤作用及其机制研究.中华肾脏病杂志,2002,18(6):398~402
21 Morii T, Fujita H, Narita T, et al. Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renaldiseases. Ren Fail, 2003, 25(3):439~444
22 何娅妮 杨聚荣 蒋建新等. Cubilin在白蛋白刺激肾小管上皮细胞表达 MCP-1、RANTES 中的作用。中华医学杂志, 2004 84(21):1804~1809
23 Wang Y, Rangan GK, Tay YC, et al .Induction of monocyte chemoattractant protein-1 by albumin is mediated by nuclear factor kappaB in proximal tubule cells. J Am Soc Nephrol, 1999, 10(6):1204~1213
24 Takaya K, Koya D, Isono M, et al. Involvement of ERK pathway in albumin-induced MCP-1 expression in mouse proximal tubular cells. Am J Physiol Renal Physiol, 2003, 284(5):F1037~1045
25 Watanabe H, Sanada H, Shigetomi S, et al. Urinary excretion of type collagen as aspeciffic indicator of the progressin of diabetic nephropathy. Nephron, 2000, 86(1):27~35
26 Wang SN, Lapage J, Hirschberg R. Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy. Kidney Int, 2000, 57(3):1002~1014
27 Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J Bio Chem, 1996, 271(30):17779~17784
28 Wada T, Furuichi K, Sakai N, et al .Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. J Am Soc Nephrol, 2004, 15(4):940~948
29 Segerer S, Cui Y, Hudkins KL, et al. Expression of the chemokine monocyte chemoattractant protein-1 and its receptor chemokine receptor 2 in human crescentic glomerulonephritis. J Am Soc Nephrol, 2000, 11(12):2231~2242
30 Lloyd CM, Dorf ME, Proudfoot A, et al. Role of MCP-1 and RANTES in inflammation and progression to fibrosis during murine crescentic nephritis. J Leukoc Biol, 1997, 62(5):676~680
31 Wada T, Furuichi K, Segawa-Takaeda C, et al. MIP-1alpha and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis. Kidney Int, 1999, 56(3):995~1003
32 Cunningham PN, Hack BK, Ren G, et al. Glomerular complement regulation is overwhelmed in passive Heymann nephritis. Kidney Int, 2001, 60(3):900~999
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3 Panzer U, Thaiss F, Zahner G, et al. Monocyte chemoattractant protein-1 and osteopontin differentially regulate monocytes recruitment in experimental glomerulonephritis. Kidney Int, 2001, 59(5):1762~1769
4 Segerer S, Cui Y, Hudkins KL, et al. Expression of the chemokine monocyte chemoattractant protein-1 and its receptor chemokine receptor 2 in human crescentic glomerulonephritis. J Am Soc Nephrol, 2000, 11(12):2231~2242
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27 Lloyd CM, Dorf ME, Proudfoot A, et al. Role of MCP-1 and RANTES in inflammation and progression to fibrosis during murine crescentic nephritis. J Leukoc Biol, 1997, 62(5):676~680
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29 Wada T, Furuichi K, Segawa-Takaeda C, et al. MIP-1alpha and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis. Kidney Int, 1999, 56(3):995~1003
30 Sakai N, Wada T, Furuichi K, et al. The role of monocyte chemotactic and activating factor (MCAF)/monocyte chemoattractant protein (MCP)-1 in subgroups of rapidly progressive glomerulonephritis. Nippon Jinzo Gakkai Shi, 1999,41(7):704~711
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26 Morii T, Fujita H, Narita T, et al. Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renal diseases. Ren Fail, 2003,25(3):439~444
27 Lloyd CM, Dorf ME, Proudfoot A, et al. Role of MCP-1 and RANTES in inflammation and progression to fibrosis during murine crescentic nephritis. J Leukoc Biol, 1997, 62(5):676~680
28 Kanellis J, Garcia GE, Li P, et al. Modulation of inflammation by slit protein in vivo in experimental crescentic glomerulonephritis. Am J Pathol, 2004, 165(1):341~352
29 Wada T, Furuichi K, Segawa-Takaeda C, et al. MIP-1alpha and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis. Kidney Int, 1999, 56(3):995~1003
30 Sakai N, Wada T, Furuichi K, et al. The role of monocyte chemotactic and activating factor (MCAF)/monocyte chemoattractant protein (MCP)-1 in subgroups of rapidly progressive glomerulonephritis. Nippon Jinzo Gakkai Shi, 1999,41(7):704~711
31 Liu ZH, Chen SF, Zhou H, et al. Glomerular expression of C-C chemokines in different types of human crescentic glomerulonephritis. Nephrol Dial Transplant, 2003, 18(8): 1526~1534
1 Quigg RJ, Morgsn BP, Holers VW, et al. Complement regulation in the rat glomerulus: Crry and CD59 regulate complement in glomerular mesangial and endothelial cells. Kidney Int, 1995, 48(2):412~421
2 Nangaku M, Meek PL, Pippin J, et al.. Transfected CD59 protects mesangial cells from injury induced by antibody and complement. Kidney Int, 1996,50(1):257~266
3 Tami H, Matsuo S, Fukatsu A, et al. Localization of 20-kD homologous restriction factor (HRF20) in diseased human glomeruli. An immunofluorescence study. Clin Exp Immuol, 1991, 84(2):256~262
4 Lehto T, Honkanen E,Teppo AM, et al. Urinary excretion of protectin (CD59), complement SC5b-9 and cytokines in membranous glomerulonephritis. Kidney Int, 1995, 47(5):1403~1411
5 Cunningham PN, Hack BK, Ren G, et al. Glomerular complement regulation is overwhelmed in passive Heymann nephritis. Kidney Int, 2001, 60(3):900~909
6 He C, Imai M, Song H, et al. Complement inhibitors targeted to the proximal tubule prevent injury in experimental nephrotic syndrome and demonstrate a key role for C5b-9. J Immunol, 2005,174(9):5750~5757
7 Arora M, Arora R, Tiwari SC, et al. Expression of complement regulatory proteins in diffuse proliferative glomerulonephritis. Lupus, 2000, 9(2):127~131
8 Richaud Patin Y, Perez Romano B, Carrillo Maravilla E, et al. Deficiency of red cell bound CD55 and CD59 in patients with systemic lupus erythematosus. Immunol Lett, 2003,88(2):95~99
9 Tsunoda S, Kawano M, Koni I, et al. Diminished expression of CD59 on activated CD8+ T cells undergoing apoptosis in systemic lupus erythematosus and Sjogren's syndrome. Scand J Immunol, 2000, 51(3):293~299
10 Daniel Turnberg, Marina Botto, Joanna Warren, et al. CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice J Am Soc Nephrol, 2003, 14(9):2271~2279
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2 Rovin BH, Doe N, Tan LC. Monocyte chemoattractant protein-1 levels in patients with glomerular disease. Am J Kidney Dis, 1996, 27(5):640~646
3 胡亚美, 姜载芳主编.《诸福堂实用儿科》第 7 版,人民卫生出版社,2003,1627~1628
4 Sahali D, Pawlak A, le gouvello S, et al. Transcriptional and post transcriptional alterations of IkappaBalpha in active minimal change nephritic syndrome. J Am Soc Nephrol, 2001,12(8):1648~1658
5 Cao C, Lu S, Dong C, et al. Abnormal DNA-bingding of transcription factors in minimal change nephritic syndrome. Pediatr nephrol, 2001, 16(10):790~795
6 Nelson PJ, Krensky AM. Chemokines, lymphocyte sandviruses: What goes around, comes around. Curr Opin Immunol, 1998, 10(3):265~270
7 丁涵露, 朱妙珍. MCP-1 在肾小球肾炎中的表达及其意义.第三军医大学学报, 2000, 22(1):60~63
8 Sakai N, Wada T, Furuichi K, et al. The role of monocytechemotactic and activating factor (MCAF)/monocyte chemoattractant protein (MCP)-1 in subgroups of rapidly progressive glomerulonephritis. Nippon Jinzo Gakkai Shi, 1999, 41(7):704~711
9 Haberstroh U, Pocock J, Gomez-Guerrero C, et al. Expression of the chemokines MCP-1/CCL2 and RANTES/CCL5 is differentially regulated by infiltrating inflammatory cells. Kidney Int, 2002,62(4):1264~1276
10 Prodjosudjadi W, Gerritsma JS, Klar-Mohamad N, et al. Production and cytokine-mediated regulation of monocyte chemoattractant protein-1 by human proximal tubular epithelial cells. Kidney Int, 1995, 48(5):1477~1486
11 Schwarz M, Wahl M, Resch K, et al . IFN gamma induces functional chemokine receptor expression in human mesangial cells. Clin Exp Immunol, 2002, 128(2):285~294
12 Rovin BH, Lu L, Marsh CB. Lymphocytes induce monocyte chemoattractant protein-1 production by renal cells after Fc gamma receptor cross-linking: role of IL-1beta. J Leukoc Biol, 2001, 69(3):435~439
13 Heck S, Bender K, Kullmann Metal. Kbalpha- independent down regulation of NF-κB activity by glucocorticoids receptor. EMBOJ, 1997, 16(5):4698~4707
14 Schwarz M, Radeke H, Resch K, et al. Lymphocyte-derived cytokines induce sequential expression of monocyte-and Tcell-specific chemokines in human mesangial cells. KidneyInt, 1997, 52(6):1521~1531
15 Widmer U, Manogue KR, Cerami A, et al. Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-1A, and MIP-1B, members of the chemokine superfamily of proinflammatory cytokines. J Immunol, 1993, 150(11):4996~5012
16 de Haij S, Woltman AM, Bakker AC, et al.Production of inflammatory mediators by renal epithelial cells is insensitive to glucocorticoids. Br J Pharmacol, 2002, 137(2):197~204
17 Fede C, Conti G, Chimenz R, et al. N-acetyl-β-D-glucosaminidase and beta2-microglobulin: prognostic markers in idiopathic nephritic syndrome. J Nephrol, 1999, 12(1):51~55
18 Schneider A, Panzer U, Zahner G, et al. MCP-1 mediates collagen deposition in experimental glmerulonephritis by transforming growth factor-beta. Kidney Int, 1999, 56(1):135~144
19 Panzer U, Thaiss F, Zahner G, et al. Monocyte chemoattractant protein-1 and osteopontin differentially regulate monocytes recruitment in experimental glomerulonephritis. Kidney Int, 2001, 59(5):1762-1769
20 程叙扬,李晓玫,唐嘉薇等.微小病变患者尿蛋白对肾小管上皮细胞的损伤作用及其机制研究.中华肾脏病杂志,2002,18(6):398~402
21 Morii T, Fujita H, Narita T, et al. Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renaldiseases. Ren Fail, 2003, 25(3):439~444
22 何娅妮 杨聚荣 蒋建新等. Cubilin在白蛋白刺激肾小管上皮细胞表达 MCP-1、RANTES 中的作用。中华医学杂志, 2004 84(21):1804~1809
23 Wang Y, Rangan GK, Tay YC, et al .Induction of monocyte chemoattractant protein-1 by albumin is mediated by nuclear factor kappaB in proximal tubule cells. J Am Soc Nephrol, 1999, 10(6):1204~1213
24 Takaya K, Koya D, Isono M, et al. Involvement of ERK pathway in albumin-induced MCP-1 expression in mouse proximal tubular cells. Am J Physiol Renal Physiol, 2003, 284(5):F1037~1045
25 Watanabe H, Sanada H, Shigetomi S, et al. Urinary excretion of type collagen as aspeciffic indicator of the progressin of diabetic nephropathy. Nephron, 2000, 86(1):27~35
26 Wang SN, Lapage J, Hirschberg R. Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy. Kidney Int, 2000, 57(3):1002~1014
27 Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J Bio Chem, 1996, 271(30):17779~17784
28 Wada T, Furuichi K, Sakai N, et al .Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. J Am Soc Nephrol, 2004, 15(4):940~948
29 Segerer S, Cui Y, Hudkins KL, et al. Expression of the chemokine monocyte chemoattractant protein-1 and its receptor chemokine receptor 2 in human crescentic glomerulonephritis. J Am Soc Nephrol, 2000, 11(12):2231~2242
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