摘要
目的:探讨肾炎消白方减少阿霉素肾病大鼠蛋白尿的作用,并从生化、分子生物学角度探讨其作用机理,为临床应用提供理论依据。
方法:用尾静脉一次性注射阿霉素制备肾炎蛋白尿模型,分为5组,分别为空白对照组、模型对照组、洛汀新组、肾炎消白方低剂量组、肾炎消白方高剂量组,观察7周,检测大鼠的尿肌酐、血清BUN、Scr、Alb,ELISA法检测尿β_2-MG、尿白蛋白,免疫组化检测大鼠肾脏COL-Ⅳ、LN平均面密度比,RT-PCR检测大鼠肾组织Nephrin mRNA、CD2AP mRNA的表达。
结果:实验7周末各治疗组(肾炎消白方高、低剂量组及洛汀新组)阿霉素肾病大鼠尿白蛋白/尿肌酐值下降,以肾炎消白方高剂量组最为明显(P<0.05);尿β_2-MG的含量降低,以肾炎消白方高剂量组最为明显(P<0.05);血清白蛋白含量上升,以肾炎消白方高剂量组最为明显(P<0.05);COL-Ⅳ、LN在肾组织中的表达减少,以肾炎消白方高剂量组最为明显(P<0.05);Nephrin mRNA、CD2AP mRNA在肾组织中的表达降低,以肾炎消白方高剂量组最好;肾功能无影响(P>0.05)。
结论:肾炎消白方能够在一定程度上减少阿霉素肾病大鼠尿蛋白的排泄量;减少阿霉素肾病大鼠尿β_2-MG的含量,对肾小管有保护作用;提高阿霉素肾病大鼠血清白蛋白的含量,其机制可能是减少尿中蛋白排泄量;降低于阿霉素肾病大鼠COL-Ⅳ、LN在肾组织中的表达,对肾脏纤维化有治疗作用;改善阿霉素肾病大鼠足细胞的形态,降低阿霉素肾病大鼠肾组织中Nephrin mRNA、CD2AP mRNA表达,对于受损足细胞有修复作用,从而减少尿蛋白的排泄量;中药高剂量组对于上述作用较中药低剂量组、洛汀新组疗效较好。
Objective:To test if nephritis Xiaobaifang decreases proteinuria level in experimental animals and investigate its mechanism by biochemical and molecular biological analysis to provide the basis for its clinical application.
Methods:We utilized a rat model in which nephritis is induced by one-time tail vein injection of doxorubicin.Animals were divided into five groups,namely the naive control group,model control group,Lotensin group,low-dose nephritis Xiaobaifang group and high-dose nephritis Xiaobaifang group.Seven weeks after treatment,we detected rat urine creatinine,serum BUN,Scr,Alb,urineβ_2-MG(by ELISA),proteinuria, COL-Ⅳand LN expression in kidney(by immunohistochemical staining), and nephrin mRNA and CD2AP mRNA expression in kidney tissue(by RT-PCR).
Results:At the end of 7-week observation,the ratio of proteinuria / urine creatinine values(P<0.05)were reduced in animals from all treatment group with doxorubicin-induced nephritis,and the high-dose nephritis Xiaobaifang treatment had the most significant effects(P<0.05);the urineβ_2-MG level(P<0.05)was also decreased in all treatment group,and the high-dose nephritis Xiaobaifang treatment had the most significant effects (P<0.05);the serum albumin concentration(P<0.05)was increased in all treatment group;and high-dose nephritis Xiaobaifang treatment had the most significant effects(P<0.05);the expression of both COL-Ⅳand LN in the kidney were decreased in all treatment group(P<0.05),and the high-dose nephritis Xiaobaifang treatment had the most significant effects (P<0.05);the treatment by nephritis Xiaobaifang did not affect the kidney function in rats with nephritis(P>0.05);the expression of both COL-Ⅳand LN in the kidney tissue were decreased in all treatment group(P<0.05), and the high-dose nephritis Xiaobaifang treatment had the most significant effects(P<0.05);all animals in the treatment group had attenuated foot cell damage,lower nephrin mRNA and CD2AP mRNA expression in kidney tissues,and the high-dose nephritis Xiaobaifang treatment had the most significant effects(P<0.05).
Conclusion:nephritis Xiaobaifang can reduce excretion a certain extent, decrease urineβ_2-MG level in nephrotic rats and protect tubulo;It can possibly increase serum albumin level by reducing excretion;It can attenuate COL-Ⅳand LN expression in kidney tissues,so it can treat kidney fibrosis;It can improve the foot cell morphology of nephrotic rats, by which it reduced excretion;It can reduce nephrin mRNA and CD2AP mRNA expression in kidney tissues from rats with doxorubicin-induced nephritis,repair injured foot cell,then.reduce excretion.The therapeutic effects with high-dose nephritis Xiaobaifang are better than low-dose nephritis Xiaobaifang or Lotensin.
引文
1.Garg AX,Kiberd BA,Clark WF,et al.Albuminuria and renalin sufficiency prevalence guides population scerening:Results from the NHANES Ⅲ.Kindney Int,2002,61:2165-2175
2.张路霞,左力,徐国宾等.北京市石景山地区中老年人群中慢性肾脏病的流行病学研究.中华肾脏病杂志[J],2006,22(2):67-71
3.Mallick NP,Short CD,Hunt LP.How far since Ellis? Nephron,1987:46:113
4.Hecg JE,De Jong PE,Van der Hern GK et al.Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinipril.Kidney Int,1989,36:272
5.Gansevoort R,de Zeeuw D,de Jong PE.Long-terin benefts of the antiproteinuric effect of ungiotensin-converting enzyme inhibition in nondiabetin renal diseases.AM J Kidney Dis,1993,22:202
6.Lewis EJ,Hunsicker L,Bain RP et al.For the Collaborative Study Group:The effect of angiotensin-converting-enayme inhibition on diabetic nephropathy.N Engl J Med,1993,329:1456
7.Jafar TH,Schnid CH,Landa M et al.Angiotensin- converting enzyme inhibition and progression of nondiabetic renal disease.A recta-analysis of patient-level data.Ann Intern Med,2001,135:73
8.仝小林,张志远.蛋白尿的中医治疗.中国医药学报[J],2002,17(2):115
9.刘伟,贝岩.中药辨证治疗蛋白尿探析.辽宁中医杂志[J],2005,32(3):225
10.郭立中,毛炜,刘玉宁,等.叶传蕙教授对肾炎蛋白尿的病机认识及治疗经验.中国中西医结合肾病杂志[J],2001,2(3):128
11.李亦聪,冯天保.谢桂权教授治疗慢性肾炎蛋白尿经验介绍.新中医[J],2006,38(4):16
12.沈庆法.肾脏病蛋白尿的中医论治.中国临床医生[J],2004,32(8):50
13.金劲松.邵朝弟教授治疗蛋白尿的经验.中国中西医结合肾病杂志[J],2006,7(9):501
14.张琼.黄淑芬从络病论治肾性蛋白尿.中医杂志[J],2004,46(10):745
15.邓聪.从风郁瘀论治蛋白尿.中华中医药杂志[J],2006,21(8):506
16.沈庆法.清利法治疗蛋白尿.上海中医药杂志[J],2006,40(2):23
17.袁红霞.林嫦娥.黄文政教授治疗顽固性蛋白尿经验总结.天津中医药[J],2003,20(5):18-19
18.刘宏伟,王国栋,张国强.国医匠时振声教授学术贡献撷萃.中医药学刊[J],2001,19(6):534
19.杜秋霞.叶传惠教授诊治肾性蛋白尿经验.四川中医[J],2001,19(5):4
20.黄臻.邹嘉玉.皮持衡治疗单纯肾性蛋白尿的经验.江西中医药[J],2006,(37)284:6
21.陈瑜.中医辨治小儿慢性肾炎蛋白尿七法.中医研究[J],2001,(14)5:30-31
22.卞华.吕芹.李学铭教授治疗肾性蛋白尿的经验.国医论坛[J],2003,18(6):11
23.庞莉.刘莉.周保林.贺永清主任医师治疗蛋白尿的经验,现代中医药[J],2005,3:22-23.
24.余立敏.从“肾虚毒损”治疗慢性肾炎蛋白尿血尿.中华中医药学刊[J],2007,25(5):972
25.代渊.唐章全主任医师治疗慢性肾蛋白尿经验.中医药学刊[J],2006,24(3):408-409
26.李巧颖.“通因通用”与肾炎蛋白尿的治疗.中医药学刊[J],2006,24(1):128-129
27.邹玺.熊宁宁.长期应用清热利湿和络法对慢性肾炎患者蛋白尿变化的影响.中医杂志[J],2004,45(4):266-269
28.方志传.养脾为主治疗慢性肾炎蛋白尿.湖北中医杂志[J],2001,23(8):346
29.张丽霞.升阳益气固肾化瘀治疗慢性肾炎蛋白尿疗效观察.中医药学刊[J],2006,24(5):965-966
30.李玉花.活血化瘀法在蛋白尿治疗中的运用.实用中西医结合临床[J],2005,(5)2:55-56
31.王静.补肾固涩法为主治疗蛋白尿30例.陕西中医[J],2001,22(10):590
32.吴金国,陈志龙,张黎明.急慢性肾炎中药治疗研究进展.中医药信息[J],2001,18(4):5
33.齐占华.益肾液治疗肾小球性蛋白尿疗效分析.实用中医药杂志[J],2005,21(10):585
34.梁汝钊.毛文忠.刘吉样.益肾煎治疗肾小球性蛋白尿31例.陕西中医[J],2005,26(8):75 3-754
35.练建红.刘恩棋.蒙向欣等.益肾Ⅰ方治疗肾小球性蛋白尿的临床研究.福建中医药[J],2007,3(3):1-3
36.雷作熹,罗仁,董晓蕾等.小四五颗粒对糖尿病大鼠肾保护作用研究[J].中药新药与临床药理[J],2003,14(2):93-96
37.代方国.魏敏.孙晓敏,等.小四五颗粒治疗慢性肾病蛋白尿30例临床观察[J].新中医,2007,39(8):33-34
38.何岚.王宁生.五苓散减轻阿霉素肾病大鼠蛋白尿的实验研究.中成药[J],2006,28(10):1532-1534
39.赵飞,王晓霞,程广清等.疏血通注射液治疗肾性蛋白尿69例临床观察[J].山东中医药大学学报,2007,31(4):294-295
40.李宏伟,王荣欣.升阳益胃汤治疗慢性肾病蛋白尿42例.中国中医药科技,2001,8(3):161
41.张万祥,秦建国,张荣等.参芪益肾汤治疗疗肾性蛋白尿45例观察.时珍国医国药,2007,18(6):1482-1483
42.韩进庭.自拟消蛋白饮联合西药治疗蛋白尿30例.长春中医药大学学报,2007,23(4):59
43.刘永琴,刘淮阳.成人无症状性血尿蛋白尿的临床病理分析及预.四川医学[J],2002,23(1),32
44.张悦,魏民,楚非,等.补肾活血泄浊汤对肾小球上皮细胞蛋白质和硫酸肝素蛋白多糖合成的影响.北京中医药大学学报[J],2001,24(6):22
45.曾红兵,刘晓城.火把花根对实验性肾炎大鼠肾脏病理改变的影响.中国中西医结合肾病杂志[J].2006,(7)1:13-15
46.尹莲芳,濮家伉,弓玉祥,等.黄蜀葵花对阿霉素肾病大鼠钠潴留改善作用的机 制.中华肾脏病杂志[J],1999,15(5):324-325
47.杨俊伟,戴春笋,陈朝红,等.雷公藤内酯醇对T细胞功能的影响与cAMP/PKA的关系.肾脏病与透析肾移植杂志[J],1 998,7(2):106-112
48.刘志红,戴春笋,李恒,等.雷公藤内酯醇对人近端肾小管上皮细胞单核细胞趋化因子合成的影响.肾脏病与透析肾移植杂志[J],2000,9(5):431-435
49.陈志强,方敬,刘丽,等.青藤碱对系膜增生性肾小球肾炎影响的实验研究[J].中国老年学杂志,2007,27:27-28
50.黄黎明,梁恒,邢建宇,等.山茱萸提取物对慢性肾炎小鼠的药理作用及蛋白质组学效应的实验研究.中国药理学通报[J],2004,20(10):1144-1150
51.Mundel P,Shankland SJ.Podocyte biology and response to injury.J Am Soc Nephrol,2002,13(12):3005-3015
52.Pavenstadt H,Kriz W,Kretzler M.Cell biology of the glomerular podocyte.Physiol Rev,2003,83(1):253-307
53.Shih NY,Li J,Karpitskii V,et al.Congenital nephritic syndrome in mice lacking CD2-associated protein.Science,1999,286(5438):312-315
54.Kim JM,Wu H,Green G,et al.CD2-associated Protein Haploinsufficiency Is Linked to Glomerular Disease Susceptibility.Science,2003,300(5623):1298-1300
55.Dustin ML,Olszowy MW,Holdorf AD,et al.A novella daptor protein or chestrates receptor patterning and cytoskeletal polarity in T-cell contacts.Cell,1998,94(5):667-677
56.Li C,Ruotsalainen V,Tryggvason K,et al.CD2AP is expressed with nephrin in developing podocytes and is found widely immature kidney and elsewhere.Am J Physiol Renal Physiol,2000,279(4):785-792
57.Gassier N,Elger M,Kranzlin B,et al.Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the fa/fa Zucker rat.Kidney Int,2001,60:106-116
58.White KE,Bilous RW,Marshall SM,et al.Podocyte number innormotensive typeldiabetic patients with albuminuria.Diabetes,2002,51(10):3083-3089
59.White KE,Bilous RW,Diabiopsies Study Group.Structural alterations to the podocyte are related to proteinuria in type 2 diabetic patients.Nephrol Dial Transplant,2004,19(6):1437-1440
60.Coward RJ,Foster RR,Patton D,et al.Nephrotic plasma alters slit diaphragm dependent signaling and translocates nephrin,Podocin,and CD2 associated protein in cultured human podocytes.J Am Soc Nephrol,2005,16(3):629-637
61.Woroniecki RP,Schiffer M,Shaw AS,et al.Glomerular expression of transforming growth factor-beta(TGF-beta)isoforms in mice lacking CD2-associated protein.Pediatr Nephrol,2006,21(3):333-338
62.Schiffer M,Bitzer M,Roberts IS,et al.Apoptosis in podocytes induced by TGF-betaandSmad7.J ClinInvest,2001,108(6):807-816
63.Schiffer M,Munde P,Shaw AS,et al.A novel role.for the adaptor molecule CD2associated protein in transforming growth factor-beta-induced apoptosis.J Biol Chem,2004,279 (35) :37004- 37012
64. Yuzawa Y,Matsuo S. Focal segmental glomerulosclerosis. Nippon Rinsho,2004,62 (10) :1837- 1841
65. Eremina V,Cui S,Gerber H,et al. Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol,2006,17 (3) :724-735
66. Kobayashi S, Sawano A,Nojima Y,et al. The c-Cbl/CD2AP complex regulates VEGF-induced endocytosis and degradation of Flt-1 ( VEGFR-1). FASEB J,2004,18 (7) :929-931
67. Huber TB,Hardeben B ,Kim J,et al. Nephrin and CD2AP associate with phosphoinositide 3 -OH kinase and stimulate AKT-dependent signailng[J]. Mol Cell Biol,2003,23(14):4917-4928
68. Cantley LC. The phosphoinositide3 -kinase pathway[J]. Science, 2002, 296 (5573 ): 1655-1657
69. Wolf G ,Stahl RA. CD 2-associated protein and glomerulard isease[J]. Lancet, 2003,362(9397):1746- 1748
70. Kim JM,Wu H , Green G,et al. CD2-associated protein haploinsuficieny is linked to glomenrlar diseases susceptibiilty[J]. Science,2003,300(5 623):1298- 1300.
71. Dikic I. CIN85/CMS family of adaptor molecules[J]. FEES Lett,2002,529 (1):110 -115
72. Soubeymn P, Kowanetz K, Szymkdewicz I, et al. Cbl-CIN85-endophdlin complex mediates ligand-induced downregulation of EGF receptors[J]. Nature, 2002, 416(6877):183- 187
73. Malissen B. Immulogy. Switching off TCR signailng[J]. Science,2003, 302(5648 ): 1162-1163
74. Johnson RJ. Am J Kid Dis,2000,36(1):214-219
75. Tryggvason K. J Am Soc Nephrod,1999,10:2440-2445
76. 胡晔时. Nephrin与蛋白尿. 国外医学. 泌尿系统分册. 2003,3:307
77. Putaala H,Soininen R,Kllpelainen P. et al. The murine nephrin gene is specifically expressed in kidney, brain and pancreas:inactivation of the gene lesds to massive pmteinuria and neonatal death[J]. Hum Mol Genet,2001,10(1):1-8
78. Routsalainen V,Patrakka J, Tissari P,et al. Am J Pathol,2000,157(6):1905- 1916
79. Topham PS, Kawachi H, Haydar SA,et al. J Clin Invest,1999,104(11):1559- 1566
80. Wang SX,Ahola H, Palmen T,et al. Exp. Nephrol,2001,9(5):327-311
81. Lee Y K,Kwon T, Kimd J,et al. Uhrastruetural study on nephfin expression in experimental puromyein aminucleoside nephmsis[J]. Nephol Dial Transplant,2004,19(12):2981-2986
82. Lahdenkar J A, Kestila M. Holmberg C,et al. Nephrin gene (NPHSI) in patients with minimal change nephrotie syndrome(MCNS)[J]. Kidney Int,2004,65 (5):1856-1863
83. Carid , Bertelli R,Diduca M. et al. Broadening the spetmm of diseases related to pedoein mutations[J].J Am See Nephol.2003,14(5):1278-1286
84.Nagahama K,Maruk,Kanzakis,et al.Possible role of utoantibodies against nephrin in an experimental model of chronic graft-versus-host disease[J].Clin Exp Immunol.2005,141(2):215-222
85.Guan N,Ding J,Deng JH,et al.Key molecular events in puremycin aminoneleside nephmsis rats[J].Pathol Int,2004,54(9):703-711
86.Saran A,Yuan H,Takeuchi E,et al.Complement mediates nephrin redistribution and actin dissociation in experimental membranous ephropathy[J].Kidney Int,2003,64(6):2072-2078
87.Bariety J,Brunevalp,Hill G,et al.Posttransplantation relapse of FSGS is characterized by glomemlar epithelial cell transdifferenticatlon[J].J Am Soe Nephol,2001,12(2):261-274
88.Kaplan JM,Kim SH,North KN,et al.Mutations in ACTN4,encoding alpha-actinin-4,cause familial focal segmental glomerulasclerosis[J].Nat Genet,2000,24:251-256
89.Yao J,Le TC,Kos CH,et al.Alpha-actinin-4-mediated FSGS:an inherited kidney disease caused by an aggre-gated and rapidly degraded cytaskeletal protein[J].Plos Biol,2004,2(6):787-794
90.Weins A,Kenlan P,Herbert S,et al.Mutational and Bio-logical Analysis of alpha-actinin-4 in focal segmental glomerulosclerosis[J].J Am Soc Nephrol.2005,16(12):3694-3701
91.Luimula P,Sandstrom N,Novikon D et al.Podocyte-associated molecules in puromycm aminonucleaside nephrosis of the rat[J].Lab Invest,2002,82(6):713-718
92.何伟春,邢昌赢,孙彬,等.CD2AP和 a-actinin-4 在大老鼠阿霉素肾病模型中的表达.南京医科大学学报(自然科学版),2006,26(11):1005-1007
93.Boute N.Gribouval O.Roselli S.et al.NPHS2.encoding the gomerular protein podocin,is mutated in autosomal recessive steroid-resistant nephrotic syndrome.Nat Genet 2000,24:349-354
94.Schwarz K.Simons M.Keiser,J.et al.Podocin,a raft-associated component of the gomemlar slit diaphragm,interacts with CD2AP and nephrin.J Clin Invest,2001,108(11):1621-1629
95.Sedeuskv MM.Siefker,JM.Mordel organisms:new insights into charnel and transporter function.Stomatiu homologues interact in Caeuorhahditis elegans.Am,J Physiol Cell Physiol.2001,280.C1340-C134R
96.Eiser J,Kriz W.The golmerular slit diaphragm is a modified adherens juntiln[J].J Am Sco Nephrol,2000,11(1):1
97.Erickson AC,Couchman JR.Still.more complexity in mammalian basement membranes.J Histochem Cytochem,2000,48(10):1291-1306
98.叶任高,沈清瑞.肾脏病诊断与治疗学.北京:北京人民卫生出版社[M],1994:208
99.叶任高,刘冠贤.临床肾脏病学.北京:北京人民卫生出版社[M],1997:52-53
100.林善琰,陈靖.肾小球疾病治疗最新进展.中国实用内科杂志,2000,20:26-29
101.Edited by Barry M.Brenner The kidneyy[J].Science press sixth dition.2000,1271-1277
102.Albert Matalon,Anthong Valeri,and Grerald B Appel:Treatment of Focal segmental Glomerulosclerosis[J].Seminars in Nephrology.2000,20:309-317
103.何敏华,叶任高,马昶云.糖皮质激素在肾小球疾病治疗中的进展.大理学院学报[J],2003,(2)3:82
104.李幼姬,叶任高,姜傥.成人原发性肾病综合征治疗的探索.中华肾脏病杂志[J],1995,11(3):133-136
105.黎磊石,张训,陈光永,等.雷公藤治疗肾小球肾炎的临床研究.中华内科杂志[J],1981,20(4):216
106.黎磊石,刘志红.雷公藤在肾脏病领域应用的前景.肾脏病与透析肾移植杂志[J],1997,6(3):203
107.施向东,范德墉,陆玉良.雷公藤多甙片对肾性蛋白尿的作用.中国中西医结合肾病杂志[J],2000,1(4),224-225
108.朱汉威,朱淳,陆玮,等.雷公藤多甙长程治疗肾小球肾炎疗效观察.上海第二医科大学学报[J],2002,22(6):543-544
109.Briggs WA,Choi MJ,Scheel PJ.Successful myco-phenolate mofetil treatment of glomerular disease.Am J Kidney Dis 1998,1(2):213
110.冯为盛,姜继元.霉酚酸酯治疗难治性肾病综合征.中华肾脏病杂志[J],1999,15(5):287
111.黄茂芹,周森,陈裕盛.霉酚酸酯治疗肾病综合征8例观察.中华肾脏病杂志[J],2000,16(6):386
112.刘光陵,高远斌,夏正坤,等.霉酚酸酯在小儿肾小球疾病治疗中的应用效果.中华儿科杂志[J],1999,37(10):640
113.沈平雁,蒋颈松.霉酚酸酯在治疗肾小球疾病中的应用.实用医学杂志[J],1999,15(9):731
114.Lou T,Wang C,Chen Z,et al.Randomised controlled trial of eflunomide in the treatment of immunoglobulin A nephropathy.Nephrology(Carlton),2006,11(2):113-116
115.王成,娄探奇,唐骅,等.来氟米特治疗难治性肾病综合征60例临床研究.中国实用内科杂志[J],2005,25(12):1096-1098
116.崔太根,侯凡凡,倪兆慧,等.来氟米特联合糖皮质激素治疗增殖型狼疮性肾炎的多中心对照临床试验研究.中华内科杂志[J],2005,44(9):672-676
117.任岳钦,李延国,马云航.来氟米特治疗过敏性紫癜性肾炎的临床研究.临床肾脏病杂志[J],2005,5(4):169-171
118.Metzler C,Fink C,Lamprecht P,et al.Maintenance of remission with leflunomide in Wegener's granulomatosis.Rheumatology(Oxford),2004,43(3):315-320
119.Xia ZK,Liu GL,Gao YF,et al.FK506 in the treatment of children with nephrotic syndrome of different pathologi-cal types[J].Clin ephrol,2006,66(2):85-88.
120.EisentackGM,et al.Kidney Int 1975,8(1):80
121.Ha H,Kim KH.Amelioration of diabetic microalbuinuria and lipid peroxidation by captopril.Yonsei Med J,1992,(33):217-273
122.Brien RC,Papazoglou D,Allen T,et al.The effects of perindopril versus triple therapy on albuminuria in normotensive diabetic rats.Kidney Int,1990,38:552-553
123.Marre M,Chatelier G,Lebianc N,et al.Prevention of diabetic nephopathy with enalapril in normotensive diabetes with microalbu-minuria.BMJ,1988,297:1092-1095
124.Burnier M,Hagman M,Nussberger J,et al.Short -Term and sustained renal effects of angiotensin Ⅱ re2 ceptor blockade in healthy subijects.Hypertension,1995,25(4 part 1):602
125.Chan J C N,Crischey J A J H,Tomlinson B,et al.Antihypertensive and antial buminuric effects of losar2 tan potassium and felodipin in Chinese elderly hyper2 tensive patients with or without non - insulin - depen2 dent diabetes mellitus.Am J Nephrol,1997,17:72
126.莫湛宇,梁东,司徒玉,等.黄芪对肾病综合征患者氧化应激影响的研究[J].中国中西医结合肾病杂志,2004,5(4):209
127.余凌,张俊峰,李惊子,等.黄芪当归合剂防治肾病综合征大鼠进行性肾小管损伤[J].中华肾脏病杂志,2000,16(5):282
128.李丽英,王海燕,朱进乐,等.黄芪当归对肾病综合征大鼠白蛋白的合成作用的研究[J].中华医学杂志,1995,75(5):276
129.苗明三,方晓艳.怀地黄多糖免疫兴奋作用的实验研究[J].中国中医药科技,2002,(3):159
130.熊玉兰,王金华,屠国瑞,等.熟地黄麦角甾苷对小鼠肾毒血清肾炎治疗作用的研究.世界科学技术一中医药现代化,2006,8(5):46-48
131.徐强,王蓉,徐丽华,等.土茯苓对细胞兔疫和体液免疫的影响.中国免疫学杂志,1993,9(1):39
132.朱南山,李丽立,张彬.党参的生物学功能及其应用前景.饲料工业,2006,(27)20:57-58
133.贺庆,朱恩圆,王峥涛.党参化学成分的研究.中医药学杂志,2006,41(1):11-12
134.田丽婷,马龙,堵年生.齐墩果酸的药理作用研究概况[J].中国中药杂志,2002,27(12):884
135.李广勋.中药药理毒理与临床[M].天津:天津科技翻译出版公司,1992.382
136.Zhang Yong-ciang,Xing-tian,Zho,Jin-huang.Effects of Ly-cium barbarum polysaccharides and their combination with Corynebacterium parvum on the tumoristaiic activity of peritoneal macrophages in mice[J].China J Phar Toxi,1989,3(3):169-174
137.周娅,佟书娟,王宁萍,等·枸杞多糖对小鼠巨噬细胞内酶活性及NO诱生的影响[J]·山东中医杂志,2000,19(6):362
138.董庆华,钟献,郑树.康莱特注射液对肺癌A549细胞环氧化酶作用的研究[J].中国中药杂志,2005,30(20):1621-1623
139.徐梓辉,周世文,黄文权,等.薏苡仁多糖对实验性糖尿病大鼠红细胞免疫、T淋 巴细胞亚群的影响[J].湖南中医学院学报,2001,21(1):17-19
140.蒋艳玲.怀山药多糖对衰老小鼠免疫器官组织的影响[J].河南中医药学刊,2002,17(6):18-19
141.肖锦松,崔风军,宁廷选,等.玉竹、菟丝子醇提物对烧伤小鼠免疫功能的影响.中国中药杂志,1990,15(9):45-47
142.叶敏,阎玉凝.菟丝子药理研究进展.北京中医药大学学报.2000,23(5):52-53
143.于庆海,杨丽君,孙启时,等.白茅根药理研究.中药材,1995,18(2):88
144.岳兴如,侯宗霞,刘萍,等.白茅根抗炎的药理作用.中国临床康复,2006,10(43):85
145.范美华,王健鑫,李鹏,等.益母草的研究进展[J].中国药物与临床,2006,6(7):528-529
146.徐勇,智光,郑思新.益母草的心血管药理作用及临床应用[J].世界急危重病医学杂志.2006.3(3):1312-1314
147.Frenk S.Experimental nephritic syndrome induced in rats by aminonucleoside.Proc Soc Exp Biol Med,1955,89:424-429
148.Diamond JR,Bonventre JV,Karnovski M.A role for oxygen free radicals in aminonucleoside nephrosis.Kidney Int,1986,29:478-483
149.Sternberg SS,Philips FS.Biphasic intoxication and nephrotic syndrome in rats given daunomycin.Proc Amer Assoc Cancer Res,1967,8:64-70
150.Egido J,Ortiz A,Gomez-Chiarri M,et al.lnvolvement of lipid mediators in the pathogenesis of experimental nephrosis in rats:its pharmacological modulation.Ren Fail,1991,13:95-101
151.Bertani T,Poggi A,Pozzoni R,et al.Adriamycin induced ne-phrotic syndrome in rats.Lab Invest,1982,46:16-23
152.Newan David J,Pugia Michael J,Lott John A,et al.Urinary protein and albunin excretion correted by creatinine and specific gravity[J].Clinica Chimica Acta,2000,294(1,2):139-155
153.Hartmann A,Jenssen T,Midtvedt K,et al.Protein-creatinine ratio-a simple method for proteinuria assessment in clinical practice[J].Tidsskrift for Den Norske Laeggforening,2002,122(22):2180-2183
154.National Kidney Foundation.K/DOQI clinical practice guidelines for chronic kidney Disease:evaluation,clawwification and stratification[J].Am J Kidney Dis,2002,39(supp 1):1-17
155.贺丹,柴华旗.黎曼.晨尿尿蛋白/尿肌酐比和24小时尿蛋白定量的临床评价.苏州大学学报(医学版).2004,24(6):861-863
156.张春荣,赵绍杰,于高权.尿β2-微球蛋白测定对原发性肾病综合征疗效判断的意义.临床荟萃,2004,19(20):1162-1163
157.Brunskill NJ.Albumin and proximal tubular cells-beyond endocytosis Nephrol Dial Transplant,2000,15:1732-1734
158.Gross ML,Hanke W,Koch.A,et al.Intraoeritoneal protein injection in the axolotl:The anphibian kidney as a novel model to study tubulointerstitial activation.Kidney Int,2002,62(1):51-59
159.Abbate M,Zoja C,Corna D,et al.In progressive nephropathies,overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation.J Am Soc Nephrol,1998,9:1231-1224
160.Eddy AA.Expression of genes that promote renal interstitial fibrosis in rats with proteinuria.Kidey Int,1996,49:S49
161.Smoyer WE,Mundel P.Regulation of podocyte(?)during the development of nephrotic syndrome.J Mol Med,1998,76(3-4):172-183
162.Lemly KV,LafayetteRA,SsfaiM,et al.Podocytopenia and disease Severity in IgA nephropathv[J]Kidney Int,2002,61(4):1475-1478
163.杜园园,黄朝兴.足突融合与IgA肾病肾小球硬化及蛋白尿的相关性分析.温州医学院学报,2007,37(3):247-249
164.Asanuma K,Mundel P.The role of podocytes in glomerular pathobiology.Clin Exp Nephrol,2003,7(4):255-259
165.张跃辉.CD2AP与肾小球滤过膜.国外医学泌尿系统分册,2004,24(5):683
166.Shih NY,Li J,Cotran R,et aI.CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain.Am J Pathol,2001,159(6):2303-2308
167.Boute N,et al.NPHS2,encoding the glomerular protein podocin,is mutat-ed in autosomal recessive steroid-resistant nephrotic syndrome.Nat Genet,2000,24,349-354
168.Matsui I,Ito T,KuriharaH,et al.Snai,l a transcriptional regulator,represses nephrin expression in glomerular epithelial cells of nephritic rats[J].Lab Invest,2007,87(3):273-283
169.Lehtonen S,Zhao F,Lehtonen E,et al.CD2-associated protein directly interacts with the actin cytoskeleton[J].Am J Physiol Renal Physiol,2002,283(4):F734-743
170.XingY,Ding J,Fan Q,et al.Diversities of podocyte molecular changes induced by different antiproteinuria drugs[J].Exp BiolMed(May-wood),2006,231(5):585-93
171.Ahola H,Wang SY,Luimula P,et al.Cloning and expression of t her at nephrin homologue[J].Am JP athol,1999,155(3):907-913
172.Boute N,Gribouval O,RoselliS,et al.NPHS2,encodingtheglomerular potein podocin,i s mutated in autosomaler cessive ster oid-resistant nephrotic syndrome[J].Nat Genet,2000,24(4):349-354
173.林丽,杨树升,朱黎明.蟾蜍干预对大鼠肾病模型CD2AP表达的影响.医学信息,2000,19(5):837-839
174.何伟春,邢昌赢,吴晓蓉,等.CD2相关蛋白mRNA在大鼠阿霉素肾病模型中的表达.江苏医药,2005,31(6):454-456
175.邢燕,丁洁,范青锋,等.三种不同药物作用下足细胞分子的变化.中华肾脏病杂志,2006,22(5):275-281