INS患儿肾组织NF-κB活性、血浆组织因子及组织因子途径抑制物的水平研究
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摘要
研究背景:原发性肾病综合征(idiopathic nephrotic syndrome,INS)是最常见的儿童肾脏疾患之一,以大量蛋白尿、低蛋白血症、高脂血症和不同程度水肿为其临床特征。糖皮质激素为目前临床治疗INS最常用药物,其疗效决定肾病的预后。大约85%～90%病例对激素敏感,尿蛋白转阴,获得临床完全缓解,这部分患儿大都预后良好;而近半数对激素耐药者则于几年内进展至终末期肾衰竭。该病迄今病因尚未完全明确。普遍认为其发病与免疫功能紊乱相关,多种炎症介质参与肾病的病理生理过程且与临床表现密切关联。核因子卡波粒(nuclear factor kappa B,NF-κB)是细胞中一个重要的核转录因子,主要由P50和P65两亚基组成,广泛存在于肾小球系膜细胞、上皮细胞及肾小管上皮细胞中。细胞静息状态下,NF-κB以无活性的形式存在于胞浆中。在特定病理因素刺激下,NF-κB被激活并易位到核内,与靶基因的启动子区域κB基序结合,参与调控多种炎症性细胞因子、趋化因子、酶和粘附分子及其受体的表达过程,在肾小球肾炎的炎症损伤与细胞再生中发挥重要作用。组织因子(tissue factor,TF)是由263个氨基酸残基组成的跨膜单链糖蛋白,正常情况下广泛存在于血管壁外膜细胞、肾纤维囊及肾小球上皮细胞。该因子转录受即早基因操纵,而后者则由NF-κB调控。TF除具有促凝血机能外,还可通过介导多种信号传导而参与肾小球炎症等病理生理过程。人体内的外源性凝血途径主要受组织因子途径抑制物(tissue factor pathway inhibitor,TFPI)调节。TFPI是存在于
Background: Idiopathic nephrotic syndrome(INS) is one of the commonest renal diseases in children,with the clinical charasteristics of intensive proteinuria, hypoalbuminemia, edema to some degree and hypercholesterolemia. Glucocortoid is the most commonly used drug at the moment and Steroid responsiveness is the major determinant of prognosis in INS. Approximately 85% to 90% of patients with INS respond to glucorticoid therapy and have complete remission of proteinuria;The rest 10% to 15% experience partial or no response to corticosteroid treatment. Children with steroid-sensitive nephrotic syndrome(SSNS)have a favorable long-term outcome, whereas half of steroid-resistant nephrotic syndrome(SRNS)patients progress to end-stage renal failure within 1 to 4 years. There are no definitely clinical predictors of the response to steroids in INS. The mechanism of INS has not yet been identified. It is generally accepted that cellular immune disturbances, particularly T-lymphocyte abnormalities, have been implicated in the pathologenesis of the disease.The absence of renal histologic alterations on light
microscopy, and no significant immune deposits in glomeruli have suggested that INS is a T-cell disorder associated with a functional renal compromise.Many inflammatory mediators including cytokines are thought to render glomerular basement membrane more permeable to proteins.The activation of nuclear factor Kappa B(NF-k B) plays a vital part in regulating the expression of these inflammatory mediators. NF-k B,composed of two subunits P50 and P65,exists extensively in mesangial, epithelial cells of glomeruli and epithelial cells of renal tubules. In resting cells, it remains in the cytoplasm in an inactive form bound to the inhibitory subunit I k B.Upon stimulation by certain pathological factors, NF-k B is translocated into the nucleus .bound to the DNA consensus sequcnce(k B site) and activates the transcription of target genes of several cytokines, chemotactic and matrix proteins that are involved in inflammatory and immunologic responses.As a result, NF- k B takes part in regulating the expression of these fundermental mediators, and plays a vital role in injury and renovation of immune glomerulonephritis. Tissue factor (TF),with another name of coagulative factor III, is a single-chain transmembrane glycoprotein composed of 263 amino acid residues generated by such cells as endothelial eel Is,platelets and macrophages/monocytes,and exists abundantly in endothelial cells of vessels,renal fibrocyst and glomerular epithelium.lt is one of the most potent initiators of the blood coagulation system which acts as a cofactor for factor VII.When stimulated by certain pathological factors,TF is produced and released into the circulation to trigger extrinsic coagulation.NF-k B regulates the transcription and expression of TF as well as immediate early genes.Besides
procoagulative function,TF is also conceived to be involved in the pathogenesis of glomerulonephritis and prethromblic state of INS, through mediating the transduction of many cellular signals. In addition, tissue factor pathway inhibitor(TFPI),as an endogenous anticoagulant, regulates the coagulatory function of tissue factor by forming two complex: FXa-TFPI-FVIIa-TF and FXa-TFPI.To our knowledge,quite a few experimental researches have been conducted to investigate the effects of activated NF-k B and TF pathway on renal diseases and some achievements of experimental models of renal injury acquired.But few combined studies were carried out on the activity of NF- k B and plasma levels of TF-TFPI system in children with idiopathic nephrotic syndrome,and their relationship with different histopathological and clinical categories of it.This study is aimed to explore the significance of abnormal activation of NF-k B in the kidney,plasma antigen of tissue factor and tissue factor pathway inhibitor in the pathophysiology and advance of childhood INS ,thus provides a theoretical basis for clinical diagnosis and administration.Materials and methods:patients and control subjects: From August 2002 to January 2005,69 children with INS,diagnosed according to the criteria, were adopted in our study. 41 of them were boys and 28 girls with mean age of 6.5 years old(range from 2.3 to 13). All the patients were absent of such secondary glomerulonephritis as purpural nephritis and pericutaneous renal biopsy under the localization of B-ultrasound was conducted on each of them with parental informed consent, with the following results of histopathological changes: 27 children with minimal change
nephrotic syndrome(MCNS)and 42 with non-minimal change nephrotic syndrome(NMCNS, including 26 mesangial proliferative glomerulonephritis, 2 focal and segmental glomerulosclerosis, 5 membranonephrology, 7 membranoproliferativeglomerulonephritis, and 2 IgM nephrology).None of the patients who experienced renal biopsy had initiated steroid therapy or been on therapy for less than 4 weeks before puncture, including all patients with nephritic nephrotic syndrome,5 with non-selective proteinuria and the rest unfavorable response to steroid. In addition,29 children with simple nephrotic syndrome and 40 nephritic nephrotic syndrome were classified based on the clinical manifestation. Follow-up of these children revealed that 36 of them showed steroid resistant(including partial response ? no response and steroid dependent),11 complete response but frequent relapse and 19 infrequent relapse.13 age and sex-matched children receiving renal operation served as the control subjects.Samples collecting:2.7ml empty venous blood was collected into plastic tubes containing 0.3ml 3.8% sodium citrate (9 volumes blood:1 volume anticoagulant) from each child at 7 ~ 8 am in the morning, and citrated plasma was separated by centrifugation at 3000r/min for 15 minutes with a high-speed, low-temperature centrifuge, removed and frozen for use.Percutaneous renal puncture was performed on the patients and renal tissues were sent for regular pathological diagnosis and the rest embedded with paraffin for use, together with sections from normal areas of nephrectomy specimens of the controls.Detection of NF- k. B activity: Two-step immuno-histochemical staining system(Beijing Zhongshan Golden bridge
Biotechnology Co. Ltd)provides a method for measuring the activity of NF- k Bin kidney. Formalin-fixed,paraffin-embedded kidney tissue sections, each with the thickness of 4 u m , were deparaffinized and hydrated, incubated at room temperature for 10 minutes in 3% hydrogen peroxide to quench endogenous peroxidase activity,washed in PBS once for five minutes.The slides were placed in a container and covered with 0.Olmol/L sodium citrate buffer,PH 6.0,heated at middle-fire of microwave stoven for 10 minutes,al lowed to cool in the buffer for half an hour, then washed in PBS three times for 2 minutes each.The slides were incubated with mouse anti-human NF-k B P65(Santa Cruz , USA) diluted at 1:100 in PBS for 2 hours at 37 °C ,washed in PBS three times for 2 minutes. The slides were incubated for 30 minutes at room temperature with Goat anti-mouse IgG horseradish peroxidase-conjugated (Santa Cruz , USA) washed with 3 changes of PBS for 2 minutes each. Each slide was incubated in diaminobenzidine (DAB) solution until desired stain intensity developed, immediately washed with deionized H20, dehydrated through alcohol and xylenes,added with 1 drop of hismoumt, covered for microscopic observation. Measurement of plasma TF and TFPIrPlasma antigen were detected with a sandwich enzyme-linked immunosorbent assay according to the notification.ELISA plates were coated overnight at 4°C with 50uL/well of mouse antihuman monoclonal antibody of TF or TFPI ( Diagnostica Inc,USA) diluted in PBS.All further incubation were at a temperature of 37°C.Each well was blocked for 30 min with 1% of bovine serum albumin(BSA). 100u L of sample dilution was added to each well and incubated for 90 minutes.Horseradish peroxidase-conjugated mouse antihuman IgG (Diagnostica
Inc, USA) dilution was added (100uL)to each well and incubated for 150min.The plates were washed three times with 100 u L/well of PBS(pH7.40 0. 01mol/l) after coating, blocking samples and conjugate incubations.The color was developed by adding 100uL of o-phenylenediamine (8mg) in phosphate-citrate buffer containing hydrogen peroxide for 30 min.Then the reaction was teminated by adding 50u L/well of 0. 5mol/l sulphuric acid. The plate were read at 450 nm using a roboticized Elx800 microplate reader (Bio-Tek instruments INC, USA ) within 30 min.All sera samples were run in duplicate, and for each serum the optical density(0D)measured on blank wells was subtracted from the OD obtained in antigen-coated wells.Linear regression equation was deduced for the calculation of plasma levels of TF(pg/ml) and TFPI(ng/ml). The inter- and intra-assay coefficients of variations for IgG assay were <6% and <10%,respectively. Data analysisAll data are expressed as mean ± standard deviat ion(SD) . Significant differences between two groups were estimated by student's t-test, multiple comparisons by Student-Newman-Keuls(SNK,namely q test) test with the basis of one-way analysis of variance (ANOVA),and x2 test(Chi-square test) for categorical variable at specific time points. Simple linear regression was used to examine the relationship between NF-k B activity in kidney and plasma TF, and that of plasma TF and TFPI as well. A P value of less than 0.05 indicated statistical significance. The SPSS Version 11.0 program was used for all statistical calculations. Results NF-k B activity in glomeruli and renal tubules in
children with INS and the control was [ (0. 85 + 0. 10) % vs (0.21 ±0.06)%, in glomeruli] and [(38. 74 + 3.80)% vs (13. 12 + 2. 35) %, in tubules], respectively (t=22. 26 and 23. 40, respectively, y°<0. 01) ; There were statistical differences of NF- k B activity in glomeruli between MCNS, NMCNS and controls(q=l1.42, 43.26 and 40. 05, respectively, P<0.01),and so were the activation of NF-k B in renal tubules between the above three groups(P<0.01);In addition, NF-k B activity in glomeruli and renal tubules of children with nephritic nephrotic syndrome was statistically different from that of simple nephrotic syndrome(P<0.01).As a result,TF and TFPI antigen in plasma of children with INS was drastically increased compared with that of the control(P<0. 01),and the ratio of TF:TFPI as well (P<0.01) ;Children with NMCNS had higher levels of plasma TF and TFPI than those with MCNS (P<0.01 and 0. 05, respect ively. ), just the same as the ratio of TFPI:TF (P<0.01).But there was no difference of plasma TFPI between simple INS and nephritic INS(q=2.01, P>0.05), and that between MCNS and NMCNS (q = 2.65, P>0. 05) . NF-k B activity of glomeruli and renal tubules in children with INS had positive correlation with plasma TF (r=0.3681 and 0. 6055, respectively,P<0.01)and 24-hour urinary protein excretion (r=0.3870 and 0. 7031, respectively, P<0.01),while no significant correlation was observed between elevated level of plasma TFPI and TF(r=0. 1612,P>0.05).Conclusions:Up-regulated activation of NF- k B in glomeruli and renal tubules of children with INS was closely related to pathological and clinical types,and aggravated proteinuria; NF-k B induced expression of plasma TF contributed to immune
damage of kidney and prethrombotic state of INS. Elevated level of TFPI specifically inhibited TF activity incompletely.Both NF- k. B and tissue factor pathway played a crucial role in the pathogenesis of INS,and were related to clinopathological manifestations and prethrombotic state.
Background: Idiopathic nephrotic syndrome(INS) is one of the commonest renal diseases in children,with the clinical charasteristics of intensive proteinuria, hypoalbuminemia, edema to some degree and hypercholesterolemia. Glucocortoid is the most commonly used drug at the moment and Steroid responsiveness is the major determinant of prognosis in INS. Approximately 85% to 90% of patients with INS respond to glucorticoid therapy and have complete remission of proteinuria;The rest 10% to 15% experience partial or no response to corticosteroid treatment. Children with steroid-sensitive nephrotic syndrome(SSNS)have a favorable long-term outcome, whereas half of steroid-resistant nephrotic syndrome(SRNS)patients progress to end-stage renal failure within 1 to 4 years. There are no definitely clinical predictors of the response to steroids in INS. The mechanism of INS has not yet been identified. It is generally accepted that cellular immune disturbances, particularly T-lymphocyte abnormalities, have been implicated in the pathologenesis of the disease.The absence of renal histologic alterations on light
microscopy, and no significant immune deposits in glomeruli have suggested that INS is a T-cell disorder associated with a functional renal compromise.Many inflammatory mediators including cytokines are thought to render glomerular basement membrane more permeable to proteins.The activation of nuclear factor Kappa B(NF-k B) plays a vital part in regulating the expression of these inflammatory mediators. NF-k B,composed of two subunits P50 and P65,exists extensively in mesangial, epithelial cells of glomeruli and epithelial cells of renal tubules. In resting cells, it remains in the cytoplasm in an inactive form bound to the inhibitory subunit I k B.Upon stimulation by certain pathological factors, NF-k B is translocated into the nucleus .bound to the DNA consensus sequcnce(k B site) and activates the transcription of target genes of several cytokines, chemotactic and matrix proteins that are involved in inflammatory and immunologic responses.As a result, NF- k B takes part in regulating the expression of these fundermental mediators, and plays a vital role in injury and renovation of immune glomerulonephritis. Tissue factor (TF),with another name of coagulative factor III, is a single-chain transmembrane glycoprotein composed of 263 amino acid residues generated by such cells as endothelial eel Is,platelets and macrophages/monocytes,and exists abundantly in endothelial cells of vessels,renal fibrocyst and glomerular epithelium.lt is one of the most potent initiators of the blood coagulation system which acts as a cofactor for factor VII.When stimulated by certain pathological factors,TF is produced and released into the circulation to trigger extrinsic coagulation.NF-k B regulates the transcription and expression of TF as well as immediate early genes.Besides
procoagulative function,TF is also conceived to be involved in the pathogenesis of glomerulonephritis and prethromblic state of INS, through mediating the transduction of many cellular signals. In addition, tissue factor pathway inhibitor(TFPI),as an endogenous anticoagulant, regulates the coagulatory function of tissue factor by forming two complex: FXa-TFPI-FVIIa-TF and FXa-TFPI.To our knowledge,quite a few experimental researches have been conducted to investigate the effects of activated NF-k B and TF pathway on renal diseases and some achievements of experimental models of renal injury acquired.But few combined studies were carried out on the activity of NF- k B and plasma levels of TF-TFPI system in children with idiopathic nephrotic syndrome,and their relationship with different histopathological and clinical categories of it.This study is aimed to explore the significance of abnormal activation of NF-k B in the kidney,plasma antigen of tissue factor and tissue factor pathway inhibitor in the pathophysiology and advance of childhood INS ,thus provides a theoretical basis for clinical diagnosis and administration.Materials and methods:patients and control subjects: From August 2002 to January 2005,69 children with INS,diagnosed according to the criteria, were adopted in our study. 41 of them were boys and 28 girls with mean age of 6.5 years old(range from 2.3 to 13). All the patients were absent of such secondary glomerulonephritis as purpural nephritis and pericutaneous renal biopsy under the localization of B-ultrasound was conducted on each of them with parental informed consent, with the following results of histopathological changes: 27 children with minimal change
nephrotic syndrome(MCNS)and 42 with non-minimal change nephrotic syndrome(NMCNS, including 26 mesangial proliferative glomerulonephritis, 2 focal and segmental glomerulosclerosis, 5 membranonephrology, 7 membranoproliferativeglomerulonephritis, and 2 IgM nephrology).None of the patients who experienced renal biopsy had initiated steroid therapy or been on therapy for less than 4 weeks before puncture, including all patients with nephritic nephrotic syndrome,5 with non-selective proteinuria and the rest unfavorable response to steroid. In addition,29 children with simple nephrotic syndrome and 40 nephritic nephrotic syndrome were classified based on the clinical manifestation. Follow-up of these children revealed that 36 of them showed steroid resistant(including partial response ? no response and steroid dependent),11 complete response but frequent relapse and 19 infrequent relapse.13 age and sex-matched children receiving renal operation served as the control subjects.Samples collecting:2.7ml empty venous blood was collected into plastic tubes containing 0.3ml 3.8% sodium citrate (9 volumes blood:1 volume anticoagulant) from each child at 7 ~ 8 am in the morning, and citrated plasma was separated by centrifugation at 3000r/min for 15 minutes with a high-speed, low-temperature centrifuge, removed and frozen for use.Percutaneous renal puncture was performed on the patients and renal tissues were sent for regular pathological diagnosis and the rest embedded with paraffin for use, together with sections from normal areas of nephrectomy specimens of the controls.Detection of NF- k. B activity: Two-step immuno-histochemical staining system(Beijing Zhongshan Golden bridge
Biotechnology Co. Ltd)provides a method for measuring the activity of NF- k Bin kidney. Formalin-fixed,paraffin-embedded kidney tissue sections, each with the thickness of 4 u m , were deparaffinized and hydrated, incubated at room temperature for 10 minutes in 3% hydrogen peroxide to quench endogenous peroxidase activity,washed in PBS once for five minutes.The slides were placed in a container and covered with 0.Olmol/L sodium citrate buffer,PH 6.0,heated at middle-fire of microwave stoven for 10 minutes,al lowed to cool in the buffer for half an hour, then washed in PBS three times for 2 minutes each.The slides were incubated with mouse anti-human NF-k B P65(Santa Cruz , USA) diluted at 1:100 in PBS for 2 hours at 37 °C ,washed in PBS three times for 2 minutes. The slides were incubated for 30 minutes at room temperature with Goat anti-mouse IgG horseradish peroxidase-conjugated (Santa Cruz , USA) washed with 3 changes of PBS for 2 minutes each. Each slide was incubated in diaminobenzidine (DAB) solution until desired stain intensity developed, immediately washed with deionized H20, dehydrated through alcohol and xylenes,added with 1 drop of hismoumt, covered for microscopic observation. Measurement of plasma TF and TFPIrPlasma antigen were detected with a sandwich enzyme-linked immunosorbent assay according to the notification.ELISA plates were coated overnight at 4°C with 50uL/well of mouse antihuman monoclonal antibody of TF or TFPI ( Diagnostica Inc,USA) diluted in PBS.All further incubation were at a temperature of 37°C.Each well was blocked for 30 min with 1% of bovine serum albumin(BSA). 100u L of sample dilution was added to each well and incubated for 90 minutes.Horseradish peroxidase-conjugated mouse antihuman IgG (Diagnostica
Inc, USA) dilution was added (100uL)to each well and incubated for 150min.The plates were washed three times with 100 u L/well of PBS(pH7.40 0. 01mol/l) after coating, blocking samples and conjugate incubations.The color was developed by adding 100uL of o-phenylenediamine (8mg) in phosphate-citrate buffer containing hydrogen peroxide for 30 min.Then the reaction was teminated by adding 50u L/well of 0. 5mol/l sulphuric acid. The plate were read at 450 nm using a roboticized Elx800 microplate reader (Bio-Tek instruments INC, USA ) within 30 min.All sera samples were run in duplicate, and for each serum the optical density(0D)measured on blank wells was subtracted from the OD obtained in antigen-coated wells.Linear regression equation was deduced for the calculation of plasma levels of TF(pg/ml) and TFPI(ng/ml). The inter- and intra-assay coefficients of variations for IgG assay were <6% and <10%,respectively. Data analysisAll data are expressed as mean ± standard deviat ion(SD) . Significant differences between two groups were estimated by student's t-test, multiple comparisons by Student-Newman-Keuls(SNK,namely q test) test with the basis of one-way analysis of variance (ANOVA),and x2 test(Chi-square test) for categorical variable at specific time points. Simple linear regression was used to examine the relationship between NF-k B activity in kidney and plasma TF, and that of plasma TF and TFPI as well. A P value of less than 0.05 indicated statistical significance. The SPSS Version 11.0 program was used for all statistical calculations. Results NF-k B activity in glomeruli and renal tubules in
children with INS and the control was [ (0. 85 + 0. 10) % vs (0.21 ±0.06)%, in glomeruli] and [(38. 74 + 3.80)% vs (13. 12 + 2. 35) %, in tubules], respectively (t=22. 26 and 23. 40, respectively, y°<0. 01) ; There were statistical differences of NF- k B activity in glomeruli between MCNS, NMCNS and controls(q=l1.42, 43.26 and 40. 05, respectively, P<0.01),and so were the activation of NF-k B in renal tubules between the above three groups(P<0.01);In addition, NF-k B activity in glomeruli and renal tubules of children with nephritic nephrotic syndrome was statistically different from that of simple nephrotic syndrome(P<0.01).As a result,TF and TFPI antigen in plasma of children with INS was drastically increased compared with that of the control(P<0. 01),and the ratio of TF:TFPI as well (P<0.01) ;Children with NMCNS had higher levels of plasma TF and TFPI than those with MCNS (P<0.01 and 0. 05, respect ively. ), just the same as the ratio of TFPI:TF (P<0.01).But there was no difference of plasma TFPI between simple INS and nephritic INS(q=2.01, P>0.05), and that between MCNS and NMCNS (q = 2.65, P>0. 05) . NF-k B activity of glomeruli and renal tubules in children with INS had positive correlation with plasma TF (r=0.3681 and 0. 6055, respectively,P<0.01)and 24-hour urinary protein excretion (r=0.3870 and 0. 7031, respectively, P<0.01),while no significant correlation was observed between elevated level of plasma TFPI and TF(r=0. 1612,P>0.05).Conclusions:Up-regulated activation of NF- k B in glomeruli and renal tubules of children with INS was closely related to pathological and clinical types,and aggravated proteinuria; NF-k B induced expression of plasma TF contributed to immune
damage of kidney and prethrombotic state of INS. Elevated level of TFPI specifically inhibited TF activity incompletely.Both NF- k. B and tissue factor pathway played a crucial role in the pathogenesis of INS,and were related to clinopathological manifestations and prethrombotic state.
引文
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34 Zoja C,Donadelli R,Colleoni S, et al. Protein overload stimulates RANTES production by proximal tubular cells depending on NF-kB activation[J].Kidney Int, 1998, 53(6) : 1608-1615.
35 Donadelli R, Abbate M, Zanchi C, et al. Protein traffic activates NF-kB gene signaling and promotes MCP-1 dependent interstitial inflammation [J]. Am J Kidney Dis, 2000, 36(6) : 1226-1241.
36 Wang Y,Rangan GK,Tay YC,et al. Induction of monocyte chemoattractant protein-1 by albumin is mediated by nuclear
factor kappa B in proximal tubule cells[J]. J Am Soc Nephrol,1999,10(6):1204-1213.
37 Wada T, Furuichi K, Sakai N, et al. Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy[J]. Kidney Int, 2000, 58(4) : 1492-1499.
38 Remuzzi G,Ruggenenti P,Benigni A. Understanding the nature of renal disease progression[J]. Kidney Int, 1997,51 (1) :2-15.
39 Gomez GC,Lepoz FO,Suzuki Y, et al.Nitric oxide production in renal cells by immune complex:role of kinases and nuclear factor-kappa B[J].Kidney Int,2002,62 (6) :2022-2034.
40 Tomita N, Morishita R,Lan HY,et al.In vivo administration of a nuclear transcription factor -Kappa B decoy suppresses experimental cresentic glomerulonephritis[J].J Am Soc Nephrol,2000, 11 (7) :1244-12 52.
41 Lopez FO,Suzuki Y, Sanjuan G, et al.Nuclear factor-Kappa B inhibitors as potential novel anti-inflammatory agents for the treat of immune glomerulonephritis[J].Am J Pathol, 2002, 161(4):1497-1505.
42 Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination : the control of NF-k B activity[J].Ann Rev Immunol, 2000, 18(1) : 621-663.
43 Nitschke R,Henger A,Risken S, et al.Angiotensin II increases the intracellular calcium activity in podocytes of the intact glomerulus[J].Kidney Int,2000,57 (1):41-49.
44 Brasier AR.Transcriptional regulation of angio-tensinogen gene expression[J]. Vitam Horm,1999,57:217-247.
45 Esteban V.Effect of simultaneous blockade of AT1 and AT2 receptors on the NK-Kappa B pathway and renal inflammatory
response[J].Kidney Int Suppl, 2003,86:S33-38.
46 Fuchshuber A, Jeanssen F, Gnbouval O, et al. Presymptomatic diagnosis of familial steroid-resistant nephrotic syndrome[J].Lancet, 1996,347(9007):1050-1051.
47 Bray PJ, Du B, Mejia VM, et al. Glicocortoid resistance caused by reduced expression of the glucocortoid receptor in cells from human vascular lesion[J].Arterioscler Thromb Vasc Biol,1999,19(5):1180-1189.
48 Scheinman RI, Cogswell PC, Lofquist AK, et al. Role of transcriptional activation of I κ Bα in mediation of immunosuppression by glucocorticoids[J]. Science, 1995,270(5234):283-286.
49 Mckay LI, Cidlowski JA. Molecular control of immune/inflammatory responses:interactions between nuclear factor-kappa B and steroid receptor-signaling pathways[J]. Endocr Rev, 1999,20(4):435-439.
50 陈诗书,汤雪明.基因表达的调控[M].医学细胞与分子生物学.上海:上海医科大学出版社,1995,429-431.
51 孙丽,丁小强,邹建洲等.INS患者GR、NF-κB和AP-1水平与糖皮质激素治疗的关系[J].复旦学报(医学版),2003,30(5):418-421.
52 Fede C, Conti G, Chimenz R, et al.N-acetyl-beta-D glucosaminidase and beta2-microglobulin:prognostic markers in idiopathic nephrotic syndrome[J].J Nephrol, 1999,12(1):51-55.
53 Mastroianni Kirsztajn G, Nishida SK, Silva MS , et al. Urinary retinol binding protein as a prognostic marker in the treatment of nephrotic syndrome[J].Nephron, 2000,86(2): 109-114.
54 Mezzano SA, Barria M, Alejandra DM, et al. Tubular NF-κB and AP-1 activation in human proteinuric renal disease[J].Kidney Int, 2001,60(4):1366-1377.
55 Cao C, Lu S, Dong C, et al. Abnormal DNA-binding of transcription factors in minimal change nephrotic syndrome[J].Pediatr Nephrol,2001,16(2):790-795.
56 Morrissey JJ, Klahr. Enalapril decreases nuclear factor κ B activation in the kidney with ureteral obstruction[J].Kidney Int, 1997,52(4):926-933.
57 Hiscott J, Kwon H, Genin P. Hostile takeovers:viral appropriation of the NF-κ B pathway[J].J Clin Invest, 2001,107(2):143-151.
58 Yamazaki S, Muta T, rakeshige K.A novel I κ B protein I κ B-zeta, induced by proinflammatory stimuli,negatively regulates nuclear factor-κ B in the nuclei[J].J Biol Chem, 2001,276(29):27657-27662.
59 Versteeg HH .tissue factor as an evolutionary conserved cytokine receptor: Implications for inflammation and signal transduction[J].Semin Hematol, 2004,41(Suppll):168-172.
60 Osterud B. rissue factor:a complex biological role[J].Thromb Haemost, 1997,78(1):755-758.
61 Muller AM, Cronen C, Muller KM, et al. Comparative analysis of the reactivity of human umbilical vein endothelial cells in organ and monolayer culture[J]. Pathobiology, 1999,67(2):99-107.
62 De Meyer GRY, Herman AG. Vascular endothelial dysfunction. Prog Cardiovasc Dis, 1997,39(4):325-342.
63 Brown NJ, Vaughan DE. Prothrombotic effects of angiotensin[J].Adv Intern Med, 2000,45:419-429.
64 Grandaliano G, Gesualdo L, Ranieri E, et al. Tissue factor, plasminogen activator inhibitor-l, and thrombin receptor expression in human crescentic glomerulonephritis[J]. Am J Kidney Dis, 2000,35(4):726-738.
65 Cunningham MA, Kitching AR, Tipping PG, et al. Fibrin independent proinflammatory effects of tissue factor in experimental crescentic glomerulonephritis[J].Kidney Int, 2004,66(2):647-654.
66 Schoenmakers SH, Versteeg HH, Groot AP, et al. Tissue factor haploinsufficiency during endotoxin induced coagulation and inflammation in mice[J].Thromb Haemost, 2004,2(12):2185-2193.
67 Sase T, Wada H, KamikuraY, et al.Tissue factor messenger RNA levels in leukocytes compared with tissue factor antigens in plasma from patients in hypercoagulable state caused by various diseases[J].Thromb Haemost, 2004,92(1):132-139.
68 Aras O, Bach RR, Hysjulien JL, et al. Induction of microparticle and cell-associated intravascular tissue factor in human endotoxemia[J].Blood, 2004, 103(12):4545-4553.
69 Grabowski EF, Reininger AJ, Petteruti PG, et al. Shear stress decreases endothelial cells tissue factor activity by augmenting secretion of tissue factor pathwy inhibitor[J].Arterioscler Thromb Vasc Biol, 2001,21(1):157-162.
70 何美霞,何晓凡,解勤之等.血管紧张素Ⅱ对单核细胞组织因子表达的影响及调控机制[J].中华血液学杂志,2003,24(9):470-473.
71 Dorffel Y, Latsch C, Stuhlmuller B, et al. Preactivated peripheral blood monocytes in patients with essential hypertension[J].Hypertension, 1999,34(1):113-117.
72 Versteeg HH. Tissue factor as an evolutionary conserved cytokine receptor: Implications for inflammation and signal transduction[J].Semin Hematot, 2004,41(1 Suppll):168-172.
73 Imamura T. Tissue factor expression at the site of inflammation: a cross-talk between inflammation and the blood coagulation system[J].Rinsho Byori, 2004,52(4):342-349.
74 Crawley J, Andrew F, Westmuckett D, et al. Expression, localization, and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels[J].Arteioscler tbromb vasc boil, 2000,20:1362-1373.
75 董临江,彭运生,王润杰等.肝脏炎性疾病患者血浆中组织因子途径抑制物与抗凝血酶Ⅲ的表达与临床意义[J].中华肝脏病杂志,1999,7(4):224-225.
76 岳少杰,钟乐,何晓凡等.新生儿感染性黄疸血浆组织因子和组织因子途径抑制物含量的变化[J].中华儿科杂志,2003,41(2):104-106.
77 Morange PE, Renucci JF, Charles MA, et al. Plasma levels of free and total TFPI, relationship with cardiovascular risk factor and endothelial cells markers[J].Thromb Haemost, 2001,85(6):999-1003.
78 吴雪海,江观玉,干建新等.闭合性颅脑损伤后组织因子、组织因子途径抑制物的动态变化及其意义[J].中华创伤杂志,2002,18(8):489—491.
79 Levi M, van der Poll T, ten Cate H, et al. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest, 1997,27(1):3-9.
80 Falciani M, Gori AM, Fedi S, et al. Elevated tissue factor and tissue factor pathway inhibitor circulating levels in ischemic heart disease patients[J].Thromb Haemost, 1998,79(3):495-499.
81 Jude B, Susen S, Flan B, et al. Detection of monocyte tissue factor after endotoxin stimulation: comparison of one functional and three immunological methods[J].Thromb Res, 1995,79(1):65-72.
82 Jeske W, Hoppensteadt D, Fareed J, et al. Measurement of functional and immunologic levels of tissue factor pathway inhibitor:Some methodologic considerations[J].Blood Coagul Fibrinolysis, 1995,6(Suppll):S73-80.
83 Zhao SP, Li J, Xu Z, et al. Fenofibrate inhibits thrombogenic and fibrinolytic factors expression in adipose tissue of atherosclerotic rabbits[J].Clin Chim Acta, 2004,349(1-2):81-86.
84 文志斌,熊石龙,何晓凡等.急性脑梗死发作期间组织因子途径改变的观察[J].中国危重病急救医学,2003,15(9):529—531.
85 Fareed J, Leong WL, Hoppensteadt DA, et al. Genetic low-molecular-weight-heparins:some practical considerations[J].Semin Thromb Hemost, 2004,30(6):703-713.
86 Kaiser B, Fareed J. Recombinant full-length tissue factor pathway inhibitor (TFPI) prevents thrombus formation and rethrombosis after lysis in a rabbit model of jugular vein thrombosis[J].Thromb Haemost, 1996,76(4):615-620
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19 Cunningham MA, Kitching AR, Tipping PG, et al. Fibrin independent proinflammatory effects of tissue factor in experimental crescentic glomerulonephritis[J]. Kidney Int, 2004,66(2) :647-654.
20 Cunningham MA, Ono T, Hewitson TD, et al. Tissue factor pathway inhibitor expression in human crescentic glomerulonephritis[J].Kidney Int, 1999, 55(4) :1311-1318.
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26 Kamitsuji H, Nonami K, Mlurakami T, et al. Elevated tissue factor circulating levels in children with hemolytic uremic syndrome caused by verotoxin-producing E. coli [J]. Cl in Nephrol, 2000,53(5) :319-324.
27 Eddy AA, Schnaper HW. The nephrotic syndrome:from the simple to the complex[J].Semin Nephrol, 1998, 18(3) :304-316.
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29 Massy ZA,Guijarro C,O' Donnell MP,et al.The central role of nuclear factor-kappa B in mesangial cell activation[J]. Kidney Int Suppl, 1999,71:S76-79.
30 Sakurai H,Shigemori N,Hisada Y,et al.Suppression of NF-kappa B and AP-1 activation by glucocorticoids in experimental glomerulonephritis in rats:molecular mechanisms of antinephritic act ion[J].Biochim Biophys Acta, 1997, 1362(2-3) :252-262.
31 Auwardt RB, Mudge SJ, Chen CG,et al. Regulation of nuclear factor kappa B by corticosteroids in rat mesangial cells[J]. J Am Soc Nephrol, 1998,9 (9) :1620-1628.
32 Ruiz-Ortega M,Bustos C,Hernandez-Presa MA,et al.Angiotensin Ⅱ participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 synthesis[J].J Tmmunol, 1998, 161 (1) :430-439.
33 Tomita N,Morishita R, Lan HY, et al.in vivo anministration of a nuclear transcription factor-kappa B decoy suppresses experimental crescentic glomerulonephritis[J].J Am Soc Nephrol,2000,11(7):1244-1252.
34 Zoja C,Donadelli R,Colleoni S, et al. Protein overload stimulates RANTES production by proximal tubular cells depending on NF-kB activation[J].Kidney Int, 1998, 53(6) : 1608-1615.
35 Donadelli R, Abbate M, Zanchi C, et al. Protein traffic activates NF-kB gene signaling and promotes MCP-1 dependent interstitial inflammation [J]. Am J Kidney Dis, 2000, 36(6) : 1226-1241.
36 Wang Y,Rangan GK,Tay YC,et al. Induction of monocyte chemoattractant protein-1 by albumin is mediated by nuclear
factor kappa B in proximal tubule cells[J]. J Am Soc Nephrol,1999,10(6):1204-1213.
37 Wada T, Furuichi K, Sakai N, et al. Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy[J]. Kidney Int, 2000, 58(4) : 1492-1499.
38 Remuzzi G,Ruggenenti P,Benigni A. Understanding the nature of renal disease progression[J]. Kidney Int, 1997,51 (1) :2-15.
39 Gomez GC,Lepoz FO,Suzuki Y, et al.Nitric oxide production in renal cells by immune complex:role of kinases and nuclear factor-kappa B[J].Kidney Int,2002,62 (6) :2022-2034.
40 Tomita N, Morishita R,Lan HY,et al.In vivo administration of a nuclear transcription factor -Kappa B decoy suppresses experimental cresentic glomerulonephritis[J].J Am Soc Nephrol,2000, 11 (7) :1244-12 52.
41 Lopez FO,Suzuki Y, Sanjuan G, et al.Nuclear factor-Kappa B inhibitors as potential novel anti-inflammatory agents for the treat of immune glomerulonephritis[J].Am J Pathol, 2002, 161(4):1497-1505.
42 Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination : the control of NF-k B activity[J].Ann Rev Immunol, 2000, 18(1) : 621-663.
43 Nitschke R,Henger A,Risken S, et al.Angiotensin II increases the intracellular calcium activity in podocytes of the intact glomerulus[J].Kidney Int,2000,57 (1):41-49.
44 Brasier AR.Transcriptional regulation of angio-tensinogen gene expression[J]. Vitam Horm,1999,57:217-247.
45 Esteban V.Effect of simultaneous blockade of AT1 and AT2 receptors on the NK-Kappa B pathway and renal inflammatory
response[J].Kidney Int Suppl, 2003,86:S33-38.
46 Fuchshuber A, Jeanssen F, Gnbouval O, et al. Presymptomatic diagnosis of familial steroid-resistant nephrotic syndrome[J].Lancet, 1996,347(9007):1050-1051.
47 Bray PJ, Du B, Mejia VM, et al. Glicocortoid resistance caused by reduced expression of the glucocortoid receptor in cells from human vascular lesion[J].Arterioscler Thromb Vasc Biol,1999,19(5):1180-1189.
48 Scheinman RI, Cogswell PC, Lofquist AK, et al. Role of transcriptional activation of I κ Bα in mediation of immunosuppression by glucocorticoids[J]. Science, 1995,270(5234):283-286.
49 Mckay LI, Cidlowski JA. Molecular control of immune/inflammatory responses:interactions between nuclear factor-kappa B and steroid receptor-signaling pathways[J]. Endocr Rev, 1999,20(4):435-439.
50 陈诗书,汤雪明.基因表达的调控[M].医学细胞与分子生物学.上海:上海医科大学出版社,1995,429-431.
51 孙丽,丁小强,邹建洲等.INS患者GR、NF-κB和AP-1水平与糖皮质激素治疗的关系[J].复旦学报(医学版),2003,30(5):418-421.
52 Fede C, Conti G, Chimenz R, et al.N-acetyl-beta-D glucosaminidase and beta2-microglobulin:prognostic markers in idiopathic nephrotic syndrome[J].J Nephrol, 1999,12(1):51-55.
53 Mastroianni Kirsztajn G, Nishida SK, Silva MS , et al. Urinary retinol binding protein as a prognostic marker in the treatment of nephrotic syndrome[J].Nephron, 2000,86(2): 109-114.
54 Mezzano SA, Barria M, Alejandra DM, et al. Tubular NF-κB and AP-1 activation in human proteinuric renal disease[J].Kidney Int, 2001,60(4):1366-1377.
55 Cao C, Lu S, Dong C, et al. Abnormal DNA-binding of transcription factors in minimal change nephrotic syndrome[J].Pediatr Nephrol,2001,16(2):790-795.
56 Morrissey JJ, Klahr. Enalapril decreases nuclear factor κ B activation in the kidney with ureteral obstruction[J].Kidney Int, 1997,52(4):926-933.
57 Hiscott J, Kwon H, Genin P. Hostile takeovers:viral appropriation of the NF-κ B pathway[J].J Clin Invest, 2001,107(2):143-151.
58 Yamazaki S, Muta T, rakeshige K.A novel I κ B protein I κ B-zeta, induced by proinflammatory stimuli,negatively regulates nuclear factor-κ B in the nuclei[J].J Biol Chem, 2001,276(29):27657-27662.
59 Versteeg HH .tissue factor as an evolutionary conserved cytokine receptor: Implications for inflammation and signal transduction[J].Semin Hematol, 2004,41(Suppll):168-172.
60 Osterud B. rissue factor:a complex biological role[J].Thromb Haemost, 1997,78(1):755-758.
61 Muller AM, Cronen C, Muller KM, et al. Comparative analysis of the reactivity of human umbilical vein endothelial cells in organ and monolayer culture[J]. Pathobiology, 1999,67(2):99-107.
62 De Meyer GRY, Herman AG. Vascular endothelial dysfunction. Prog Cardiovasc Dis, 1997,39(4):325-342.
63 Brown NJ, Vaughan DE. Prothrombotic effects of angiotensin[J].Adv Intern Med, 2000,45:419-429.
64 Grandaliano G, Gesualdo L, Ranieri E, et al. Tissue factor, plasminogen activator inhibitor-l, and thrombin receptor expression in human crescentic glomerulonephritis[J]. Am J Kidney Dis, 2000,35(4):726-738.
65 Cunningham MA, Kitching AR, Tipping PG, et al. Fibrin independent proinflammatory effects of tissue factor in experimental crescentic glomerulonephritis[J].Kidney Int, 2004,66(2):647-654.
66 Schoenmakers SH, Versteeg HH, Groot AP, et al. Tissue factor haploinsufficiency during endotoxin induced coagulation and inflammation in mice[J].Thromb Haemost, 2004,2(12):2185-2193.
67 Sase T, Wada H, KamikuraY, et al.Tissue factor messenger RNA levels in leukocytes compared with tissue factor antigens in plasma from patients in hypercoagulable state caused by various diseases[J].Thromb Haemost, 2004,92(1):132-139.
68 Aras O, Bach RR, Hysjulien JL, et al. Induction of microparticle and cell-associated intravascular tissue factor in human endotoxemia[J].Blood, 2004, 103(12):4545-4553.
69 Grabowski EF, Reininger AJ, Petteruti PG, et al. Shear stress decreases endothelial cells tissue factor activity by augmenting secretion of tissue factor pathwy inhibitor[J].Arterioscler Thromb Vasc Biol, 2001,21(1):157-162.
70 何美霞,何晓凡,解勤之等.血管紧张素Ⅱ对单核细胞组织因子表达的影响及调控机制[J].中华血液学杂志,2003,24(9):470-473.
71 Dorffel Y, Latsch C, Stuhlmuller B, et al. Preactivated peripheral blood monocytes in patients with essential hypertension[J].Hypertension, 1999,34(1):113-117.
72 Versteeg HH. Tissue factor as an evolutionary conserved cytokine receptor: Implications for inflammation and signal transduction[J].Semin Hematot, 2004,41(1 Suppll):168-172.
73 Imamura T. Tissue factor expression at the site of inflammation: a cross-talk between inflammation and the blood coagulation system[J].Rinsho Byori, 2004,52(4):342-349.
74 Crawley J, Andrew F, Westmuckett D, et al. Expression, localization, and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels[J].Arteioscler tbromb vasc boil, 2000,20:1362-1373.
75 董临江,彭运生,王润杰等.肝脏炎性疾病患者血浆中组织因子途径抑制物与抗凝血酶Ⅲ的表达与临床意义[J].中华肝脏病杂志,1999,7(4):224-225.
76 岳少杰,钟乐,何晓凡等.新生儿感染性黄疸血浆组织因子和组织因子途径抑制物含量的变化[J].中华儿科杂志,2003,41(2):104-106.
77 Morange PE, Renucci JF, Charles MA, et al. Plasma levels of free and total TFPI, relationship with cardiovascular risk factor and endothelial cells markers[J].Thromb Haemost, 2001,85(6):999-1003.
78 吴雪海,江观玉,干建新等.闭合性颅脑损伤后组织因子、组织因子途径抑制物的动态变化及其意义[J].中华创伤杂志,2002,18(8):489—491.
79 Levi M, van der Poll T, ten Cate H, et al. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest, 1997,27(1):3-9.
80 Falciani M, Gori AM, Fedi S, et al. Elevated tissue factor and tissue factor pathway inhibitor circulating levels in ischemic heart disease patients[J].Thromb Haemost, 1998,79(3):495-499.
81 Jude B, Susen S, Flan B, et al. Detection of monocyte tissue factor after endotoxin stimulation: comparison of one functional and three immunological methods[J].Thromb Res, 1995,79(1):65-72.
82 Jeske W, Hoppensteadt D, Fareed J, et al. Measurement of functional and immunologic levels of tissue factor pathway inhibitor:Some methodologic considerations[J].Blood Coagul Fibrinolysis, 1995,6(Suppll):S73-80.
83 Zhao SP, Li J, Xu Z, et al. Fenofibrate inhibits thrombogenic and fibrinolytic factors expression in adipose tissue of atherosclerotic rabbits[J].Clin Chim Acta, 2004,349(1-2):81-86.
84 文志斌,熊石龙,何晓凡等.急性脑梗死发作期间组织因子途径改变的观察[J].中国危重病急救医学,2003,15(9):529—531.
85 Fareed J, Leong WL, Hoppensteadt DA, et al. Genetic low-molecular-weight-heparins:some practical considerations[J].Semin Thromb Hemost, 2004,30(6):703-713.
86 Kaiser B, Fareed J. Recombinant full-length tissue factor pathway inhibitor (TFPI) prevents thrombus formation and rethrombosis after lysis in a rabbit model of jugular vein thrombosis[J].Thromb Haemost, 1996,76(4):615-620