吡格列酮对糖尿病大鼠肾脏形态及JNK信号通路的影响
摘要
目的:本研究旨在观察胰岛素增敏剂吡格列酮对伴胰岛素抵抗的糖尿病(diabetes mellitus,DM)大鼠的肾脏结构及c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)蛋白的表达的影响,并探讨其保护DM大鼠肾脏的机制,为糖尿病肾脏病变的防治提供新思路。
方法:①将长期高脂喂养、伴胰岛素抵抗(insulin resistance,IR)的DM大鼠随机分为模型组、吡格列酮(pioglitazone,PIO)组,PIO组予吡格列酮10mg/kg.d灌胃给药;②治疗6周后颈椎脱臼处死大鼠,取多块肾脏新鲜组织放入冻存管在液氮罐中保存备用。制备肾脏组织石蜡切片。取肾脏组织匀浆,?20℃储存备用;③HE、PAS、Masson’s、PASM染色后观察各组大鼠的肾脏病理情况。④免疫组化对JNK,p-JNK进行半定量分析;⑤逆转录聚合酶链反应(reverse transcription-polymerase chain raction ,RT-PCR)测定JNKmRNA在肾脏中的表达;⑥Westem免疫印迹方法定量分析JNK,p-JNK蛋白的表达。
结果:肾脏病理:HE、PAS、Masson’s、PASM染色后观察,与NC组对比,DM组的肾小囊腔狭小,肾小球体积增大,胶原增多,基底膜不规则增厚,基质增多;系膜区扩大,系膜细胞增多,有局部溶解现象;肾小管变形,管腔狭窄;肾间质不均匀伴有散在纤维化。PIO组与DM组比较:肾小球大小均匀,基底膜规则伴轻度增生,系膜区染色欠均匀,肾小管形态少数异常,肾间质未见纤维化。免疫组化:①NC组肾小球,肾小管及肾间质的JNK及P-JNK表达甚微。②DM组肾小球,肾小管及肾间质均有不同程度的JNK及P-JNK表达,与NC组相比,差异有显著性(P<0.05)③PIO组肾小球,肾小管及肾间质均有微量的JNK和P-JNK表达,与NC组相比差异无显著性(P>0.05),但与DM组相比差异有显著性(P<0.05)。RT-PCR:①在NC组中JNKmRNA几乎不表达②与NC组相比,DM组JNKmRNA的表达量明显增高③与DM组相比,PIO组JNKmRNA的表达量明显下降④PIO组与NC组相比,JNKmRNA的表达量相差不明显。WESTERN BLOT:①与DM组相比,PIO组P-JNK与总JNK蛋白的表达量均降低差异有显著性(P<0.05)②DM组与正常对照组相比P-JNK与总JNK蛋白的表达量明显升高,差异有显著性(P<0.05)③与DM组相比,PIO组P-JNK与总JNK蛋白量的比值明显降低,差异有显著性(P<0.05)④PIO组P-JNK与总JNK蛋白的表达量以及P-JNK与总JNK蛋白量的比值与正常对照相近,差异无显著性(P>0.05)。
结论:①吡格列酮能减轻糖尿病大鼠的肾脏病理状况。②正常情况下S-D大鼠肾脏JNK和p-JNK表达量很低,伴IR的T2DM肾脏组织的JNK和p-JNK表达上升明显,pJNK/JNK也有所上升。③经吡格列酮治疗后可降低JNK和p-JNK表达,同时pJNK/JNK也有所下降。④吡格列酮对伴IR的T2DM大鼠的肾脏保护作用可能与降低JNK磷酸化表达有关。
Objectives:to observe the effect of insulin sensitizer pioglitazone (PIO) on kidney of Diabetic rats with insulin resisitance,and its effect on c-Jun N-terminal kinase(JNK)expression.To probe the protective mechanism of PIO on renal function of diabetic rats and to provide a new thought for the prevention and cure of Diabetic Nephropathy.
Methods:①After animal model of diabetic rats with insulin resistance (IR)was established,rats were randomly divided into three groups: normal control group(NC),diabetes mellitus group(DM),and pioglitazone group(PIO)in which rats were treated with PIO at dose of 10mg/kg.d by intragastric administration.②Rats were executed through the method of cervical spine dislocation after 6-week’s intervention. Kidney specimens were harvested were stored in liquid nitrogen for use.③Pathological changes was observed by means of HE, PAS, Masson’s, and PASM.④JNK, p-JNK was analyzed semiquantitatively by using the method of immunol histochemistry.⑤JNK mRNA expression of kidney tissue was examined by reverse transcription-polymerase chain raction(RT-PCR).⑥Protein expression of JNK and p-JNK was examined by using Western Blot.
Results: 1.Pathological changes of kidney structure:We observed the pathological changes of rat kidney tissue in the diabetes mellitus group (DM), and found that,compared with normal control group(NC), Bowman's space of the former group became small,the size of glomeruli increased, the amount of collagen and extracellular matrix increased, and basement membrane was irregularly thickened.We also found that extra glomerularmesangial region expanded, and the amount of mesangial cells increased and part of those cells dissolved. In addition, renal tubules deformed with narrowing,and nterstitium distributed unevenly with scattered fibration.Compared with DM group,glomeruli of the PIO group were uniform,and basement membrane distributed evenly with slight hyperplasia. Besides, dyeing of extra glomerularmesangial region was uneven,and slight paramorphia was found in renal tubules, moreover there was no fibration in nterstitium. 2.Immunol histochemistry(IHC):①There was little JNK and P-JNK expression in the glomeruli , renal tubules, and nterstitium of NC group.②JNK and P-JNK expression in these three parts of DM group were variant , and compared with that of NC group the expression increased.The difference of expression levels between these two groups was statistically significant(P<0.05).③There was no statistical significance between the JNK and P-JNK expression levels of the PIO group and that of NC group(P>0.05),but compared with DM group the change level of JNK and P-JNK expression in PIO group was statistically significant(P<0.05).3.RT-PCR:①There was almost no JNK mRNA expression in NC group.②The JNK mRNA expression in DM group increased dramatically when compared with that in NC group.③JNK mRNA expression level of PIO group decreased remarkably in contrast to that of DM group.④There was no evidently difference between the JNK mRNA expression of the PIO group and that of NC group.4.Western Blot:①Compared with that of DM group ,P-JNK and JNK protein expression of PIO group decreased with statistical significance (P<0.05).②P-JNK and JNK protein expression of DM group increased dramatically when compared to that of NC group,and the difference was statistically significant(P<0.05).③The ratio of JNK protein expression level to P-JNK protein expression level in PIO group increased with statistical significance(P<0.05),compared with that in DM group.④In PIO group,JNK and P-JNK protein expression level and their ratio was similar to what we observed in NC group and there was no statistical significance(P>0.05).
Conclusions:①PIO can improve the Pathological changes of kidney structure of diabetic rats.②JNK and P-JNK are less expressed in kidney tissue of SD rat under normal condition, but their expression level are increased dramatically in kidney tissue of DM group with Insulin resistance(IR).Furthermore, the ratio of P-JNK to JNK are also increased.③JNK and P-JNK expression can be down regulated by the treatment of pioglitazone (PIO),along with the reduced ratio of P-JNK to JNK.④Suppressed expression level of phosphorylated JNK may play roles in the mechanism of the protective effect of pioglitazone(PIO)on rat kidney in DM group with insulin resistance.
方法:①将长期高脂喂养、伴胰岛素抵抗(insulin resistance,IR)的DM大鼠随机分为模型组、吡格列酮(pioglitazone,PIO)组,PIO组予吡格列酮10mg/kg.d灌胃给药;②治疗6周后颈椎脱臼处死大鼠,取多块肾脏新鲜组织放入冻存管在液氮罐中保存备用。制备肾脏组织石蜡切片。取肾脏组织匀浆,?20℃储存备用;③HE、PAS、Masson’s、PASM染色后观察各组大鼠的肾脏病理情况。④免疫组化对JNK,p-JNK进行半定量分析;⑤逆转录聚合酶链反应(reverse transcription-polymerase chain raction ,RT-PCR)测定JNKmRNA在肾脏中的表达;⑥Westem免疫印迹方法定量分析JNK,p-JNK蛋白的表达。
结果:肾脏病理:HE、PAS、Masson’s、PASM染色后观察,与NC组对比,DM组的肾小囊腔狭小,肾小球体积增大,胶原增多,基底膜不规则增厚,基质增多;系膜区扩大,系膜细胞增多,有局部溶解现象;肾小管变形,管腔狭窄;肾间质不均匀伴有散在纤维化。PIO组与DM组比较:肾小球大小均匀,基底膜规则伴轻度增生,系膜区染色欠均匀,肾小管形态少数异常,肾间质未见纤维化。免疫组化:①NC组肾小球,肾小管及肾间质的JNK及P-JNK表达甚微。②DM组肾小球,肾小管及肾间质均有不同程度的JNK及P-JNK表达,与NC组相比,差异有显著性(P<0.05)③PIO组肾小球,肾小管及肾间质均有微量的JNK和P-JNK表达,与NC组相比差异无显著性(P>0.05),但与DM组相比差异有显著性(P<0.05)。RT-PCR:①在NC组中JNKmRNA几乎不表达②与NC组相比,DM组JNKmRNA的表达量明显增高③与DM组相比,PIO组JNKmRNA的表达量明显下降④PIO组与NC组相比,JNKmRNA的表达量相差不明显。WESTERN BLOT:①与DM组相比,PIO组P-JNK与总JNK蛋白的表达量均降低差异有显著性(P<0.05)②DM组与正常对照组相比P-JNK与总JNK蛋白的表达量明显升高,差异有显著性(P<0.05)③与DM组相比,PIO组P-JNK与总JNK蛋白量的比值明显降低,差异有显著性(P<0.05)④PIO组P-JNK与总JNK蛋白的表达量以及P-JNK与总JNK蛋白量的比值与正常对照相近,差异无显著性(P>0.05)。
结论:①吡格列酮能减轻糖尿病大鼠的肾脏病理状况。②正常情况下S-D大鼠肾脏JNK和p-JNK表达量很低,伴IR的T2DM肾脏组织的JNK和p-JNK表达上升明显,pJNK/JNK也有所上升。③经吡格列酮治疗后可降低JNK和p-JNK表达,同时pJNK/JNK也有所下降。④吡格列酮对伴IR的T2DM大鼠的肾脏保护作用可能与降低JNK磷酸化表达有关。
Objectives:to observe the effect of insulin sensitizer pioglitazone (PIO) on kidney of Diabetic rats with insulin resisitance,and its effect on c-Jun N-terminal kinase(JNK)expression.To probe the protective mechanism of PIO on renal function of diabetic rats and to provide a new thought for the prevention and cure of Diabetic Nephropathy.
Methods:①After animal model of diabetic rats with insulin resistance (IR)was established,rats were randomly divided into three groups: normal control group(NC),diabetes mellitus group(DM),and pioglitazone group(PIO)in which rats were treated with PIO at dose of 10mg/kg.d by intragastric administration.②Rats were executed through the method of cervical spine dislocation after 6-week’s intervention. Kidney specimens were harvested were stored in liquid nitrogen for use.③Pathological changes was observed by means of HE, PAS, Masson’s, and PASM.④JNK, p-JNK was analyzed semiquantitatively by using the method of immunol histochemistry.⑤JNK mRNA expression of kidney tissue was examined by reverse transcription-polymerase chain raction(RT-PCR).⑥Protein expression of JNK and p-JNK was examined by using Western Blot.
Results: 1.Pathological changes of kidney structure:We observed the pathological changes of rat kidney tissue in the diabetes mellitus group (DM), and found that,compared with normal control group(NC), Bowman's space of the former group became small,the size of glomeruli increased, the amount of collagen and extracellular matrix increased, and basement membrane was irregularly thickened.We also found that extra glomerularmesangial region expanded, and the amount of mesangial cells increased and part of those cells dissolved. In addition, renal tubules deformed with narrowing,and nterstitium distributed unevenly with scattered fibration.Compared with DM group,glomeruli of the PIO group were uniform,and basement membrane distributed evenly with slight hyperplasia. Besides, dyeing of extra glomerularmesangial region was uneven,and slight paramorphia was found in renal tubules, moreover there was no fibration in nterstitium. 2.Immunol histochemistry(IHC):①There was little JNK and P-JNK expression in the glomeruli , renal tubules, and nterstitium of NC group.②JNK and P-JNK expression in these three parts of DM group were variant , and compared with that of NC group the expression increased.The difference of expression levels between these two groups was statistically significant(P<0.05).③There was no statistical significance between the JNK and P-JNK expression levels of the PIO group and that of NC group(P>0.05),but compared with DM group the change level of JNK and P-JNK expression in PIO group was statistically significant(P<0.05).3.RT-PCR:①There was almost no JNK mRNA expression in NC group.②The JNK mRNA expression in DM group increased dramatically when compared with that in NC group.③JNK mRNA expression level of PIO group decreased remarkably in contrast to that of DM group.④There was no evidently difference between the JNK mRNA expression of the PIO group and that of NC group.4.Western Blot:①Compared with that of DM group ,P-JNK and JNK protein expression of PIO group decreased with statistical significance (P<0.05).②P-JNK and JNK protein expression of DM group increased dramatically when compared to that of NC group,and the difference was statistically significant(P<0.05).③The ratio of JNK protein expression level to P-JNK protein expression level in PIO group increased with statistical significance(P<0.05),compared with that in DM group.④In PIO group,JNK and P-JNK protein expression level and their ratio was similar to what we observed in NC group and there was no statistical significance(P>0.05).
Conclusions:①PIO can improve the Pathological changes of kidney structure of diabetic rats.②JNK and P-JNK are less expressed in kidney tissue of SD rat under normal condition, but their expression level are increased dramatically in kidney tissue of DM group with Insulin resistance(IR).Furthermore, the ratio of P-JNK to JNK are also increased.③JNK and P-JNK expression can be down regulated by the treatment of pioglitazone (PIO),along with the reduced ratio of P-JNK to JNK.④Suppressed expression level of phosphorylated JNK may play roles in the mechanism of the protective effect of pioglitazone(PIO)on rat kidney in DM group with insulin resistance.
引文
1.Duncan B,Schmidt M I,Pankow J S,et al.Low grade systemic inflammation and the development of type 2 diabetes:The atherosclerosis risk in communities study[J].Diabetes,2003,52(7):1799-1805
2.Leinonen E S ,Hiukka A,Hurt Camejo E,et al.Low-grade inflammation , endothelial activation and carotid intima-media thickness in type 2 diabetes [J].J Intern Med,2004,256(2):119-127
3.Cai D,Yuan M,Frantz D F,et al.Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappa B[J].Nat Med , 2005 ,11(2):183-190.
4.胡肇衡,赵连礼,毛腾淑.合并微量白蛋白尿的非肥胖、非高血压的非胰岛素依赖型糖尿病患者的胰岛素抵抗[J].北京医科大学学报,2000,32(1);47-49.
5.Niskanen L,Laskso M.Isulin resistance is related to albummuria in patients with type 2 (non-insulin-dependent)diabetes mellitus[J].Metabolism , 1993 , 42(12): 1541-1545.
6.Liu ZH,Liu H,Peng A,et al.Amylin:a new component in the development of renal lesions in patients with type 2 diabetes mellitus[J].J Am Soc Nephrol,2001,12(12):150A.
7.Kambham N,Markowitz GS,Valeri AM et al.Obesity-related glomerulopathy:An emerging epidemic.Kidney Int,2001,59:1489
8.Chagnac A,Weinstein T,Korzets A et al.Glomerular hemodynamics in severe obesity.Am J Physiol Renal Physiol,2000,278:F817
9.Verani RR.Obesity associated local segmental glomerulosclerosis : Pathological features of the lesion and relationship with cardiomegaly and hyperlipidemia.Am J Kidney Dis,1992,20:629
10.Reaven GM.The kidney :An unwilling accomphice in syndrome X.Am J Kidney Dis,1997,30:928
11.Juan F,Navarro JF,Mora C, et al.Inflammatory parameters are independentlyassociate with urinary albumin in type 2 diabetes mellitus[J]. Am J KidneyDis, 2003,42 (1) :53 - 55.
12.Wolf G, Ziyadeh FN.Molecular mechanisms of diabetic renal hypertrophy Kidney Int,1999,56(2) :393-405.
13.廖岚,雷闽湘,陈慧玲,等,高敏c-反应蛋白与2型糖尿病肾病[J].中南大学学报(医学版),2004,29(6):627—30
14.Kumar D.Zimpelmann J,Robertson S,et a1.Tubular and interstitial cell apoptosis in the streptozotocin-diabetic rat kidney[J].Nephron Exp Nephrol,2004,96(3):e77一e88
15.Liu W,Li SX. Study progress on fiber like synovial fibroblasts of rheumatoid arthritis[J].Chin J Rheumatol,2005,9(10):620 - 2.
16.Widmann C, Gibem S, jarpe MB, et al.Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human .Physio Rev,1999,79:143-180.
17.Jiang Y (姜勇) ,Liu AH (刘爱华) ,Zhao KS (赵克森) .The signal transduction pathways of mitogen-activated proteinkinase. J First Mil Med Univ (第一军医大学学报) 1999,19(1) :59～62 (inChinese) .
18.Zhang L张璐,Jians Y姜勇,Zhang L张琳et al.Progress of study on mitogen-activated protein kinase. Foreign Med Sci:section Pathophysiol Clin Med (国外医学:生理、病理科学与临床分册),1999,19(2) :84～87 (in Chinese) .
19.Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK,JNK,and p38 protein kinases.Science,2002,298:1911-1912.
20.Kasibhatla S, Brunner T, Genestier L, et al. DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol Cell,1998,1:543-551.
21.Natali A,Baldeweg S,Tosehi E,et a1.Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes[J].Diabetes Care,2004,27(6):1349-1357.
22.Asano T,Wakisaka M,Yoshinnari M,et al.Peroxisome proliferator activated receptor gamma 1(PPARγ1) expresses in rat messengial cells and PPARγ1 agonists modulate its differentiation.Biochim Biophys Acta,2000;1497(1):148-154.
23.Ma LJ,Marcantpni C,Linton MF,et al.Peroxisome proliferator activated receptor-γagonist troglitazone protects against nondiabetic glomerulosclerosis in rats.Kidney Int,2001,59:1899-1910.
24.Kintscher U,Goetze S,Wakino S,et al. Peroxisome proliferator- activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes[ J ]. Eur J Pharmacol, 2000,401(3) : 259 - 270.
25.Chinetti G,Griglio S,AntonucciM,et al. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages[J]. J BiolChem,1998,273(40) :25573 - 25580.
26.Jiang C,Ting AT,Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines[J ]. Nature,1998,391:82 - 86.
27.Fischer B,Von Knethen A,Brune B. Dualism of oxidized lipoproteins in provoking and attenuating the oxidative burst in macrophages:role of peroxisome proliferator-activated receptor-gamma[J]. J Immunol,2002,168 (6) : 2828 - 2834.
28.Renier G, Clement I, Desfaits AC, et al. Direct stimulatory effect of insulin-like growth factor-I on monocyte and macrophage tumor necrosis factor-alpha production[J]. Endocrinology, 1996, 137:4611 - 4618.
29.Pasceri V,Wu HD,Willerson JT,et al. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators[J]. Circulation,2000,101(3) : 235 -238.
30.Chen Z, Ishibashi S, Perrey S, et al. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL [ J ]. Arterioscler Thromb Vasc Biol,2001, 21(3): 372 - 377.
31.周丽斌,陈名道.胰岛素增敏剂噻唑烷二酮类药物的研究进展[J].实用糖尿病杂志,2005;1(6):58-59.
32.张世春.噻唑烷二酮类药物的药理和临床[J].四川生理科学杂志,2005,27(3):129-130.
33.RajivA. Anti-inflammatory effects of short-term pioglitazone therapy in men with advanced diabetic nephropathy[J]. Am J Physiol Renal Physiol,2006, 290(3) :600 - 5.
34.陈丽,郭延云,章秋等。吡格列酮对T2DM大鼠肾脏超微结构及NO、CRP水平的影响。安徽医科大学学报,2007,42(5):494-497
35.孙俊英,郭延云,陈丽,等。2型糖尿病大鼠模型的建立与评价。安徽医科大学学报,2007,42(4):433-435。
36.Li R, Liu EM, Yang XQ ,et al. Effects of Bacillus Calmette-Guerin vaccination on immune functional development of splenic T cell in neonatal mice.Zhonghua Er Ke Za Zhi. 2005 Feb;43(2):124-7
37. Navarro JF, MoraC, MacaM, et al.Inflammationtory parameters are independently associated with urinary albumin in type 2 diabetes mellitus. Am J Kidney Dis,2003,42:53-61.
38.AndersHJ, VielhauerV, SchlondorffD. Chemokines and chemokine receptors are involved in the resolution orprogression of renal disease.Kidney Int, 2003,63:401-415.
39.Mensah-Brown EPK, Obineche EN, Galadari S, et al Streptozotocin-induced diabetic nephropathy in rats: The role of inflammatory cytokines. CYTOKINE, 2005, 31(3): 180-190.
40.Lee SH, Lee TW, Ihm CG, et al.Genetics of diabetic nephropathy in type 2 DM: candidate gene analysis for the pathogenic role of inflammation. Nephrology,2005,10:S32-S36.
41.Navarro JF, Mora C. Role of inflammation in diabetic complications.Nephrology dialysis transplantation, 2005, 20(12): 2601-2604.
42.Sfakianaki M, Xydakis D, Papadogiannakia A, et al.Low-gradeIn flammation is correlated to diabetic nephropathy in type 2 diabetes mellitus. Diabetologia,2005,48:A375-A376.
43.Narkunaraja S,Marpadga A,Mausumee G.High Glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic Cells.Diabetes,2003,52:1256-1264.
44.Park CW,Kim JH,Lee JW,et al.High glucose-induced intercellular adhesion molecule-1(ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-κB-dependent. Diabetologia, 2000,43: 1544-1553.
45.Lynn, EG, Siow YL.Very low density lipoprotein stimulates the expression of monocyte chemoat tractant protein-1 in mesangial cells.Kidney Int, 2000, 57(4): 1472 - 1483.
46.KodamaN, OtaniH, Yamada Y, et al.Involvement of MCP-1 and MCSF in glomerular foam cell formation in ExHC rats. Kidney Int Supp l,1999, 71: 174 - 177.
47.Yamagishi S, TakeuchiM, InagakiY, et al Role ofadvanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic microangiopathy. Int J Clin Pharmacol Res,2003,23(4): 129-34.
48. Morii T, Fujita H, Narita T, et al. Association of monocyte chemoat tractant protein-1 with renal tublar damage in diabetic nephropathy.J Diabetes Complications, 2003, 17(1): 11-15
49. Sugimoto H, Shikata K, Hirata K, et al.Increased expression of intercellular adhesionmolecule-1 (ICAM-1) in diabetic ratglomerul:i glomerular hyperfiltration is a potentialmechanism of ICAM-1 upregulation. Diabetes. 1997,46(12):2075-81.
50. Banba N, Nakamura T, Matsumura M, et al.Possible relationship of monocyte chemoattractant protein-1 with diabetic nephropathy.Kidney Int, 2000, 58: 684-690.
51.Kitada M, Koya D, Sugimoto T, et al. Translocation of glomerular p47phox and p67phox by protein kinase C-activation is required for oxidative stress in diabetic nephropathy. Diabetes, 2003,52: 2603-2614.
52.Hashimoto H, Kitagawa K, Hougaku H, et al. C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis.Circulation,2001,104:63-67.
53.Tamaki K,Okuda S.Role of TGF-beta in the progression of Renal fibrosis J.Contrib Nephrol,2003,139(1):44-65.
54. Chen S,Hong SW,Iglesias-de la cruz MC,et al.The key Role of transforming growth factor-beta system in the pathogenesis of diabetic nephropathy J.Ren Fail,2001,23 (3-4) :471-481.
55. Hayashida T,Decaestecker M,Schnaper HW.Cross-talk Between ERK MAP kinase and Smad Signaling pathways enhances TGF-beta dependent responses in human mesangial cells J.FASEB,2003,17(1):1576-1578.
56.Isono M,Crug M,Chen S,et al.Extracellular signal-regulated kinase mediates stimulation of TGF-beta and matrix by high glucose in mesangial cells J.J Am Soc Nephrol,2000,11(12):2222-2230.
57.Kaneto H, Nakatani Y, Kawamori D,et al. Involvement of oxidative stress and the JNK pathway in glucose toxicity. Rev Diabet Stud. 2004,1(4):165-174.
58.Kaneto H ,Xu G,Fujii N , et al. Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J Biol Chem,2002 ,277(33):30010-30018.
59.Major CD,Wolf BA.Interleukin-I beta stimulation of c-Jun NH(2)-terminal kinase activity in insulin-secreting cells: evidence for cytoplasmic restriction. Diabetes,2001,50;2721-2728.
60.Ammendrup A, Maillard A, Nielsen K,etal.The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells. Diabetes. 2000 Sep;49(9):1468-76.
61.Bonny C, Oberson A, Steinmann M, etal.IB1 reduces cytokine-induced apoptosis of insulin-secreting cells.J Biol Chem. 2000;275(22):16466-72.
62.Haefliger JA, Tawadros T, Meylan L.et al.The scaffold protein IB1/JIP-1 is a critical mediator of cytokine-induced apoptosis in pancreatic beta cells..J Cell Sci. 2003,15;116:1463-9.
63.Bonny C, Oberson A, Negri S, et al.Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death.Diabetes. 2001 Jan;50(1):77-82.
64.Saltiel AR,Kahn CR.Insulin signalling and the regulation of glucose and lipid metabolism.Nature,2001,414(6865):799-806.
65.Fletcher B,Lamendola C.Insulin resistance syndrome.J Cardiovasc Nurs,2004,19(5):339-345.
66.Nakatani Y,Kaneto H,Kawamori D,et al.Modulation of the JNK pathway in liver affects insulin resistance status.J Biol Chem,2004,279 (44):45803-45809.
67.Hirosumi J,Tuncman G,Chang L,et al.A central role for JNK in obesity and insulin resistance.Nature,2002,420(6913):333-336.
68.Saltiel AR,Olefsky JM.ThiazoIidinediones in the treatment of insulin resistance and type II diabetes.Diabetes,1996,45(12):1661-1669.
69.孙海艳,屈会起,邱明才。吡格列酮对链脲佐菌素诱导的糖尿病大鼠肾脏保护作用研究.中华内科杂志,2003,42(8):579-580.
70.阮昱,李红,郑芬萍,等。吡格列酮对糖尿病大鼠肾脏转化生长因子β1及Ⅳ型胶原表达的作用.中华糖尿病杂志,2004,12(5):373-376.
71.董凤芹,李红,蔡卫民,等。吡格列酮对糖尿病大鼠肾组织基质金属蛋白酶2和9表达的影响.中华内分泌代谢杂志,2004,20(5):459-460。
72.孙子林,任晓妹,金晖,等。余叶蓉吡格列酮对2型糖尿病肾病患者血清AGE-肽和MCP-1的影响。江苏医药,2006,32(2):101-103。
73. Tanimoto M,Fan Q,Gohda T,et a1.Effect of pioglitazone on the early stage of type 2 diabetic nephropathy in KK / Ta mice metabolism[J].Metabolism,2004,53(11):1473-9.
74. Bakris G,Viberti G,Weston W M ,et a1.Rosiglitazone reduces urinary albumin excretion in type 2 diabetes[J].J HumHypertens,2003,17(1):7-12.
75. Nakamura T,Ushiyama C,Osada S, et al. Pioglitazone Reduces urinary podocyte excretion in type2 diabetes patients with microalbuminuria J.Metabolism,2001,50(10) :1193-1196.
76.Isshiki K,Haneda M,Koya D, et al.Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats J.Diabetes,2000,49 (6) :1022-1032.
1.鲁谨,邹大进.新一代抗糖尿病药物-胰岛素增敏剂[J],上海医院药学,1998,9(2):142-17.
2.Kraegen EW, James DE, Jenkins DJ, et al. A potent in vivo effectsof ciglitazone on muscle insulin resistance induced by high fat feding in rats[J]. metabolism,1989, 38: 1086.
3.Castle CK, Colca JR, Melchior GW. Lipoprotein profile characterization of the KKA mouse, a rodentmodel of type II diabetes,before and after treatment with the insulin sensitizing agent pioglitazone[J]. Arterioscler Thromb,1992, 13: 307.
4.The Control and Complication Trial Research Group。The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-depentment diabetes mellitus〔J〕1N EnglMed,1993: 329-42.
5.Prospective Diabetes Study (UPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes〔J〕.Lancet,1998; 352: 837-45.
6.Willian IS.Lipotoxicity and glucotoxicity in type 2 diabetes〔J〕.Post- Graduate Medicine, 2001; 109: 55-845
7.陈雅静.Ⅳ型胶原酶与糖尿病肾病〔J〕国外医学·内分泌分册2002; 22 (4) : 256-8.
8.何冰,韩萍,吕先科.2型糖尿病患者急性时相蛋白与糖尿病肾病的关系[J].中华内分泌代谢杂志,2003,19(4):260
9.陈玲.肾素-血管紧张素系统与糖尿病肾病研究进展〔J〕.国外医学·泌尿系统分册, 2002; 22 (6) : 378-81.
10.Zilin S ,Naifeng L ,Bicheng L ,et al . The determination of AGEpeptides by flow injection assay , a practical marker of diabetic nephropathy. Clin Chim Acta ,2001 ,313 :69-75.
11.刘颖慧. TNF2α与糖尿病肾病〔J〕.国外医学·内分泌分册,2002; 22 (4) : 253-5
12.Giampietro O,Matteucci E,Pedrineli R Erythrocyte sodium hydrogen exchange and microalbuminuria in type 1 diabetes[J].Diabetes Care.2000;19:995-8.
13.Hultberg B.The excrection of N-acety B—glucosaminidase inglomerulonephritis[J].Clin Nephrol,2003;9:32-6.
14.Tanimoto M,Fan Q,Gohda T,et a1.Effect of pioglitazone on the early stage of type 2 diabetic nephropathy in KK/Ta mice metabolism [J]. Metabolism,2004,53(11):1473-9.
15.Bakris G,Viberti G,Weston W M ,et a1.Rosiglitazone reduces urinary albumin excretion in type 2 diabetes[J].J HumHypertens,2003,17(1):7-12.
16. Asano T,Wakisaka M,Yoshinnari M,et al.Peroxisome proliferator activated receptor gamma 1(PPARγ1) expresses in rat messengial cells and PPARγ1 agonists modulate its differentiation.Biochim Biophys Acta,2000;1497(1):148-154.
17. Ma LJ,Marcantpni C,Linton MF,et al.Peroxisome proliferator activated receptor-γagonist troglitazone protects against nondiabetic glomerulosclerosis in rats.Kidney Int,2001,59:1899-1910.
18.Kumar D.Zimpelmann J,Robertson S,et a1.Tubular and interstitial cell apoptosis in the streptozotocin-diabetic rat kidney[J].Nephron Exp Nephrol,2004,96(3):e77一e88
19.张艳玲,段惠军,李春香,等.糖尿病大鼠肾脏细胞凋亡与Bax和Bcl一2基因表达[J].中国糖尿病杂志,2002,10(3):159-162.
20.王先令,陆菊明.血糖波动对糖尿病预后及其慢性并发症发生发展的影响[J].国外医学:内分泌学分册,2005,25(3):169-173
21.Guan Y,Zhang Y,Schneider A,et a1.Peroxisome proliferators_activated receptor-gamma activeity is associated with renal microvasculature [J].Am J Physiol Renal Physiol,2001,281(6):F1036-F1046
22.Saltiel AR,Olefsky JM.ThiazoIidinediones in the treatment of insulin resistance and type II diabetes.Diabetes,1996,45(12):1661-1669.
23.李延兵,廖志红,黄知敏,等.吡格列酮和二甲双胍对2型糖尿病胰岛素抵抗的影响.中华内分泌代谢杂志,2004,20(1):30—32
24.余叶蓉,李延兵,樊继援,等.吡格列酮与二甲双胍治疗2型糖尿病的疗效比较.中华内分泌代谢杂志,2003,19(3):232-234.
25.Shichiri M, Kishikawa H, Ohkubo Y, et al. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabeticpatients [ J] . Diabetes Care, 2000, 23( Suppl 2) : B21- B29.
26.孙子林,任晓妹,金晖,等。余叶蓉吡格列酮对2型糖尿病肾病患者血清AGE-肽和MCP-1的影响。江苏医药,2006,32(2):101-103。
27 .Martens FM ,Visseren FL,Lemay J,et a1.Metabolic and additional vascular effects of thiazolidinediones.Drugs,2002,62:1463-1480.
28 .Goldberg RB, Kendall DM, Deeg MA,et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005 Jul;28(7):1547-54.
29. Paffen E,Demaat M P.C-reactive protein in atherosclerosis:A causal factor?[J].Cardio-Vasc Res,2006,71(1):30-9.
30 .Singh U,Devaraj S,Jialal I,et a1.C-reactive protein decreases tissue plasminogen activator activity in human aortic endothelial cells evidence that C-reactive protein is a procoagula[J].Arterioscler Thromb Vasc Boil,2005,25(10):2216-21.
31. Verma S,Li S H,Badiwala M V,et a1.Endothelin antagonism and Interleukin-6 inhibition attenuate the proatherogenic effects of C.reactive protein[J].Circulation,2002,105(16):1890-6.
32.廖岚,雷闽湘,陈慧玲,等,高敏c-反应蛋白与2型糖尿病肾病[J].中南大学学报(医学版),2004,29(6):627-30
33.Stehouwer C D,Gall M A,Twisk J W,et al,Increased urinary a1bumin excretion,endothelial dysfunction and chronic low-grade inflammation in type 2 diab etes:Progressive,interrelated,and independently associated with risk of death[J] Diabetes,2002,51(4):1157-65
34. Zheng F,Fomoni A,Elliot SJ,et a1.Upregulation of type I collagen by TGF-beta in mesangial cells is blocked by PPARgamma activation.Am J Physiol Renal Physiol,2002.282:F639一F648.
35.孙海艳,屈会起,邱明才.吡格列酮对链脲佐菌素诱导的糖尿病大鼠肾脏保护作用研究.中华内科杂志,2003,42(8):579-580.
36.阮昱,李红,郑芬萍,等.吡格列酮对糖尿病大鼠肾脏转化生长因子β1及Ⅳ型胶原表达的作用.中华糖尿病杂志,2004,12(5):373-376.
37.董凤芹,李红,蔡卫民,等.吡格列酮对糖尿病大鼠肾组织基质金属蛋白酶2和9表达的影响.中华内分泌代谢杂志,2004,20(5):459-460。
38. McLennan SV, Yue DK, Turtle JR,et al. Effect of glucose on matrix metalloproteinase activity in mesangial cells. Nephron. 1998;79(3):293-8.
39. McLennan SV, Martell SY, Yue DK,et al. High glucose concentration inhibits the expression of membrane type metalloproteinase by mesangial cells: possible role in mesangium accumulation. Diabetologia. 2000 May;43(5):642-8.
40. Lupia E, Elliot SJ, Lenz O,et al. IGF-1 decreases collagen degradation in diabetic NOD mesangial cells: implications for diabetic nephropathy. Diabetes. 1999 Aug;48(8):1638-44.
41. Nicholas SB, Kawano Y, Wakino S,et al. Expression and function of peroxisome proliferator-activated receptor-gamma in mesangial cells. Hypertension. 2001 Feb;37(2 Part 2):722-727.
42.Zilin S ,Naifeng L ,Bicheng L ,et al . The determination of AGE-peptides by flow injection assay , a practical marker of diabetic nephropathy. Clin Chim Acta ,2001 ,313 :69-75.
43.Nakamura T ,Matsuda T , Kawagoe Y,et al . Effect of pioglitazone on carotid intima-media thickness and arterial stiffness in type 2 diabetic nephropathy patients. Metabolism , 2004 , 53 :1382-1386.
44.Parulkar A,Pendergrass ML,Granda-Ayala。et a1.Nonhypoglycemic effects of thiazolidinediones [J].Ann Intern Med.2001,134(1):61-67.
45.Pistrosch F,Pssauer J,Fischer S,et a1.In type 2 diabetes,rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control[J].Diabetes Care,2004,27(2):484-490.
46.Natali A,Baldeweg S,Tosehi E,et a1.Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes[J].Diabetes Care,2004。27(6):1349-1357.
47.Boyle PJ,King AB,Olansky L,et a1.Effects of pioglitazone and rosiglitazoneon blood lipid levels and glycemie control in patients with type 2 diabetes mllitus:a retrospective review of randomly selected medical records[J].Clin Ther,2002.24(3):378-396
2.Leinonen E S ,Hiukka A,Hurt Camejo E,et al.Low-grade inflammation , endothelial activation and carotid intima-media thickness in type 2 diabetes [J].J Intern Med,2004,256(2):119-127
3.Cai D,Yuan M,Frantz D F,et al.Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappa B[J].Nat Med , 2005 ,11(2):183-190.
4.胡肇衡,赵连礼,毛腾淑.合并微量白蛋白尿的非肥胖、非高血压的非胰岛素依赖型糖尿病患者的胰岛素抵抗[J].北京医科大学学报,2000,32(1);47-49.
5.Niskanen L,Laskso M.Isulin resistance is related to albummuria in patients with type 2 (non-insulin-dependent)diabetes mellitus[J].Metabolism , 1993 , 42(12): 1541-1545.
6.Liu ZH,Liu H,Peng A,et al.Amylin:a new component in the development of renal lesions in patients with type 2 diabetes mellitus[J].J Am Soc Nephrol,2001,12(12):150A.
7.Kambham N,Markowitz GS,Valeri AM et al.Obesity-related glomerulopathy:An emerging epidemic.Kidney Int,2001,59:1489
8.Chagnac A,Weinstein T,Korzets A et al.Glomerular hemodynamics in severe obesity.Am J Physiol Renal Physiol,2000,278:F817
9.Verani RR.Obesity associated local segmental glomerulosclerosis : Pathological features of the lesion and relationship with cardiomegaly and hyperlipidemia.Am J Kidney Dis,1992,20:629
10.Reaven GM.The kidney :An unwilling accomphice in syndrome X.Am J Kidney Dis,1997,30:928
11.Juan F,Navarro JF,Mora C, et al.Inflammatory parameters are independentlyassociate with urinary albumin in type 2 diabetes mellitus[J]. Am J KidneyDis, 2003,42 (1) :53 - 55.
12.Wolf G, Ziyadeh FN.Molecular mechanisms of diabetic renal hypertrophy Kidney Int,1999,56(2) :393-405.
13.廖岚,雷闽湘,陈慧玲,等,高敏c-反应蛋白与2型糖尿病肾病[J].中南大学学报(医学版),2004,29(6):627—30
14.Kumar D.Zimpelmann J,Robertson S,et a1.Tubular and interstitial cell apoptosis in the streptozotocin-diabetic rat kidney[J].Nephron Exp Nephrol,2004,96(3):e77一e88
15.Liu W,Li SX. Study progress on fiber like synovial fibroblasts of rheumatoid arthritis[J].Chin J Rheumatol,2005,9(10):620 - 2.
16.Widmann C, Gibem S, jarpe MB, et al.Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human .Physio Rev,1999,79:143-180.
17.Jiang Y (姜勇) ,Liu AH (刘爱华) ,Zhao KS (赵克森) .The signal transduction pathways of mitogen-activated proteinkinase. J First Mil Med Univ (第一军医大学学报) 1999,19(1) :59～62 (inChinese) .
18.Zhang L张璐,Jians Y姜勇,Zhang L张琳et al.Progress of study on mitogen-activated protein kinase. Foreign Med Sci:section Pathophysiol Clin Med (国外医学:生理、病理科学与临床分册),1999,19(2) :84～87 (in Chinese) .
19.Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK,JNK,and p38 protein kinases.Science,2002,298:1911-1912.
20.Kasibhatla S, Brunner T, Genestier L, et al. DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol Cell,1998,1:543-551.
21.Natali A,Baldeweg S,Tosehi E,et a1.Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes[J].Diabetes Care,2004,27(6):1349-1357.
22.Asano T,Wakisaka M,Yoshinnari M,et al.Peroxisome proliferator activated receptor gamma 1(PPARγ1) expresses in rat messengial cells and PPARγ1 agonists modulate its differentiation.Biochim Biophys Acta,2000;1497(1):148-154.
23.Ma LJ,Marcantpni C,Linton MF,et al.Peroxisome proliferator activated receptor-γagonist troglitazone protects against nondiabetic glomerulosclerosis in rats.Kidney Int,2001,59:1899-1910.
24.Kintscher U,Goetze S,Wakino S,et al. Peroxisome proliferator- activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes[ J ]. Eur J Pharmacol, 2000,401(3) : 259 - 270.
25.Chinetti G,Griglio S,AntonucciM,et al. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages[J]. J BiolChem,1998,273(40) :25573 - 25580.
26.Jiang C,Ting AT,Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines[J ]. Nature,1998,391:82 - 86.
27.Fischer B,Von Knethen A,Brune B. Dualism of oxidized lipoproteins in provoking and attenuating the oxidative burst in macrophages:role of peroxisome proliferator-activated receptor-gamma[J]. J Immunol,2002,168 (6) : 2828 - 2834.
28.Renier G, Clement I, Desfaits AC, et al. Direct stimulatory effect of insulin-like growth factor-I on monocyte and macrophage tumor necrosis factor-alpha production[J]. Endocrinology, 1996, 137:4611 - 4618.
29.Pasceri V,Wu HD,Willerson JT,et al. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators[J]. Circulation,2000,101(3) : 235 -238.
30.Chen Z, Ishibashi S, Perrey S, et al. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL [ J ]. Arterioscler Thromb Vasc Biol,2001, 21(3): 372 - 377.
31.周丽斌,陈名道.胰岛素增敏剂噻唑烷二酮类药物的研究进展[J].实用糖尿病杂志,2005;1(6):58-59.
32.张世春.噻唑烷二酮类药物的药理和临床[J].四川生理科学杂志,2005,27(3):129-130.
33.RajivA. Anti-inflammatory effects of short-term pioglitazone therapy in men with advanced diabetic nephropathy[J]. Am J Physiol Renal Physiol,2006, 290(3) :600 - 5.
34.陈丽,郭延云,章秋等。吡格列酮对T2DM大鼠肾脏超微结构及NO、CRP水平的影响。安徽医科大学学报,2007,42(5):494-497
35.孙俊英,郭延云,陈丽,等。2型糖尿病大鼠模型的建立与评价。安徽医科大学学报,2007,42(4):433-435。
36.Li R, Liu EM, Yang XQ ,et al. Effects of Bacillus Calmette-Guerin vaccination on immune functional development of splenic T cell in neonatal mice.Zhonghua Er Ke Za Zhi. 2005 Feb;43(2):124-7
37. Navarro JF, MoraC, MacaM, et al.Inflammationtory parameters are independently associated with urinary albumin in type 2 diabetes mellitus. Am J Kidney Dis,2003,42:53-61.
38.AndersHJ, VielhauerV, SchlondorffD. Chemokines and chemokine receptors are involved in the resolution orprogression of renal disease.Kidney Int, 2003,63:401-415.
39.Mensah-Brown EPK, Obineche EN, Galadari S, et al Streptozotocin-induced diabetic nephropathy in rats: The role of inflammatory cytokines. CYTOKINE, 2005, 31(3): 180-190.
40.Lee SH, Lee TW, Ihm CG, et al.Genetics of diabetic nephropathy in type 2 DM: candidate gene analysis for the pathogenic role of inflammation. Nephrology,2005,10:S32-S36.
41.Navarro JF, Mora C. Role of inflammation in diabetic complications.Nephrology dialysis transplantation, 2005, 20(12): 2601-2604.
42.Sfakianaki M, Xydakis D, Papadogiannakia A, et al.Low-gradeIn flammation is correlated to diabetic nephropathy in type 2 diabetes mellitus. Diabetologia,2005,48:A375-A376.
43.Narkunaraja S,Marpadga A,Mausumee G.High Glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic Cells.Diabetes,2003,52:1256-1264.
44.Park CW,Kim JH,Lee JW,et al.High glucose-induced intercellular adhesion molecule-1(ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-κB-dependent. Diabetologia, 2000,43: 1544-1553.
45.Lynn, EG, Siow YL.Very low density lipoprotein stimulates the expression of monocyte chemoat tractant protein-1 in mesangial cells.Kidney Int, 2000, 57(4): 1472 - 1483.
46.KodamaN, OtaniH, Yamada Y, et al.Involvement of MCP-1 and MCSF in glomerular foam cell formation in ExHC rats. Kidney Int Supp l,1999, 71: 174 - 177.
47.Yamagishi S, TakeuchiM, InagakiY, et al Role ofadvanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic microangiopathy. Int J Clin Pharmacol Res,2003,23(4): 129-34.
48. Morii T, Fujita H, Narita T, et al. Association of monocyte chemoat tractant protein-1 with renal tublar damage in diabetic nephropathy.J Diabetes Complications, 2003, 17(1): 11-15
49. Sugimoto H, Shikata K, Hirata K, et al.Increased expression of intercellular adhesionmolecule-1 (ICAM-1) in diabetic ratglomerul:i glomerular hyperfiltration is a potentialmechanism of ICAM-1 upregulation. Diabetes. 1997,46(12):2075-81.
50. Banba N, Nakamura T, Matsumura M, et al.Possible relationship of monocyte chemoattractant protein-1 with diabetic nephropathy.Kidney Int, 2000, 58: 684-690.
51.Kitada M, Koya D, Sugimoto T, et al. Translocation of glomerular p47phox and p67phox by protein kinase C-activation is required for oxidative stress in diabetic nephropathy. Diabetes, 2003,52: 2603-2614.
52.Hashimoto H, Kitagawa K, Hougaku H, et al. C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis.Circulation,2001,104:63-67.
53.Tamaki K,Okuda S.Role of TGF-beta in the progression of Renal fibrosis J.Contrib Nephrol,2003,139(1):44-65.
54. Chen S,Hong SW,Iglesias-de la cruz MC,et al.The key Role of transforming growth factor-beta system in the pathogenesis of diabetic nephropathy J.Ren Fail,2001,23 (3-4) :471-481.
55. Hayashida T,Decaestecker M,Schnaper HW.Cross-talk Between ERK MAP kinase and Smad Signaling pathways enhances TGF-beta dependent responses in human mesangial cells J.FASEB,2003,17(1):1576-1578.
56.Isono M,Crug M,Chen S,et al.Extracellular signal-regulated kinase mediates stimulation of TGF-beta and matrix by high glucose in mesangial cells J.J Am Soc Nephrol,2000,11(12):2222-2230.
57.Kaneto H, Nakatani Y, Kawamori D,et al. Involvement of oxidative stress and the JNK pathway in glucose toxicity. Rev Diabet Stud. 2004,1(4):165-174.
58.Kaneto H ,Xu G,Fujii N , et al. Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J Biol Chem,2002 ,277(33):30010-30018.
59.Major CD,Wolf BA.Interleukin-I beta stimulation of c-Jun NH(2)-terminal kinase activity in insulin-secreting cells: evidence for cytoplasmic restriction. Diabetes,2001,50;2721-2728.
60.Ammendrup A, Maillard A, Nielsen K,etal.The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells. Diabetes. 2000 Sep;49(9):1468-76.
61.Bonny C, Oberson A, Steinmann M, etal.IB1 reduces cytokine-induced apoptosis of insulin-secreting cells.J Biol Chem. 2000;275(22):16466-72.
62.Haefliger JA, Tawadros T, Meylan L.et al.The scaffold protein IB1/JIP-1 is a critical mediator of cytokine-induced apoptosis in pancreatic beta cells..J Cell Sci. 2003,15;116:1463-9.
63.Bonny C, Oberson A, Negri S, et al.Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death.Diabetes. 2001 Jan;50(1):77-82.
64.Saltiel AR,Kahn CR.Insulin signalling and the regulation of glucose and lipid metabolism.Nature,2001,414(6865):799-806.
65.Fletcher B,Lamendola C.Insulin resistance syndrome.J Cardiovasc Nurs,2004,19(5):339-345.
66.Nakatani Y,Kaneto H,Kawamori D,et al.Modulation of the JNK pathway in liver affects insulin resistance status.J Biol Chem,2004,279 (44):45803-45809.
67.Hirosumi J,Tuncman G,Chang L,et al.A central role for JNK in obesity and insulin resistance.Nature,2002,420(6913):333-336.
68.Saltiel AR,Olefsky JM.ThiazoIidinediones in the treatment of insulin resistance and type II diabetes.Diabetes,1996,45(12):1661-1669.
69.孙海艳,屈会起,邱明才。吡格列酮对链脲佐菌素诱导的糖尿病大鼠肾脏保护作用研究.中华内科杂志,2003,42(8):579-580.
70.阮昱,李红,郑芬萍,等。吡格列酮对糖尿病大鼠肾脏转化生长因子β1及Ⅳ型胶原表达的作用.中华糖尿病杂志,2004,12(5):373-376.
71.董凤芹,李红,蔡卫民,等。吡格列酮对糖尿病大鼠肾组织基质金属蛋白酶2和9表达的影响.中华内分泌代谢杂志,2004,20(5):459-460。
72.孙子林,任晓妹,金晖,等。余叶蓉吡格列酮对2型糖尿病肾病患者血清AGE-肽和MCP-1的影响。江苏医药,2006,32(2):101-103。
73. Tanimoto M,Fan Q,Gohda T,et a1.Effect of pioglitazone on the early stage of type 2 diabetic nephropathy in KK / Ta mice metabolism[J].Metabolism,2004,53(11):1473-9.
74. Bakris G,Viberti G,Weston W M ,et a1.Rosiglitazone reduces urinary albumin excretion in type 2 diabetes[J].J HumHypertens,2003,17(1):7-12.
75. Nakamura T,Ushiyama C,Osada S, et al. Pioglitazone Reduces urinary podocyte excretion in type2 diabetes patients with microalbuminuria J.Metabolism,2001,50(10) :1193-1196.
76.Isshiki K,Haneda M,Koya D, et al.Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats J.Diabetes,2000,49 (6) :1022-1032.
1.鲁谨,邹大进.新一代抗糖尿病药物-胰岛素增敏剂[J],上海医院药学,1998,9(2):142-17.
2.Kraegen EW, James DE, Jenkins DJ, et al. A potent in vivo effectsof ciglitazone on muscle insulin resistance induced by high fat feding in rats[J]. metabolism,1989, 38: 1086.
3.Castle CK, Colca JR, Melchior GW. Lipoprotein profile characterization of the KKA mouse, a rodentmodel of type II diabetes,before and after treatment with the insulin sensitizing agent pioglitazone[J]. Arterioscler Thromb,1992, 13: 307.
4.The Control and Complication Trial Research Group。The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-depentment diabetes mellitus〔J〕1N EnglMed,1993: 329-42.
5.Prospective Diabetes Study (UPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes〔J〕.Lancet,1998; 352: 837-45.
6.Willian IS.Lipotoxicity and glucotoxicity in type 2 diabetes〔J〕.Post- Graduate Medicine, 2001; 109: 55-845
7.陈雅静.Ⅳ型胶原酶与糖尿病肾病〔J〕国外医学·内分泌分册2002; 22 (4) : 256-8.
8.何冰,韩萍,吕先科.2型糖尿病患者急性时相蛋白与糖尿病肾病的关系[J].中华内分泌代谢杂志,2003,19(4):260
9.陈玲.肾素-血管紧张素系统与糖尿病肾病研究进展〔J〕.国外医学·泌尿系统分册, 2002; 22 (6) : 378-81.
10.Zilin S ,Naifeng L ,Bicheng L ,et al . The determination of AGEpeptides by flow injection assay , a practical marker of diabetic nephropathy. Clin Chim Acta ,2001 ,313 :69-75.
11.刘颖慧. TNF2α与糖尿病肾病〔J〕.国外医学·内分泌分册,2002; 22 (4) : 253-5
12.Giampietro O,Matteucci E,Pedrineli R Erythrocyte sodium hydrogen exchange and microalbuminuria in type 1 diabetes[J].Diabetes Care.2000;19:995-8.
13.Hultberg B.The excrection of N-acety B—glucosaminidase inglomerulonephritis[J].Clin Nephrol,2003;9:32-6.
14.Tanimoto M,Fan Q,Gohda T,et a1.Effect of pioglitazone on the early stage of type 2 diabetic nephropathy in KK/Ta mice metabolism [J]. Metabolism,2004,53(11):1473-9.
15.Bakris G,Viberti G,Weston W M ,et a1.Rosiglitazone reduces urinary albumin excretion in type 2 diabetes[J].J HumHypertens,2003,17(1):7-12.
16. Asano T,Wakisaka M,Yoshinnari M,et al.Peroxisome proliferator activated receptor gamma 1(PPARγ1) expresses in rat messengial cells and PPARγ1 agonists modulate its differentiation.Biochim Biophys Acta,2000;1497(1):148-154.
17. Ma LJ,Marcantpni C,Linton MF,et al.Peroxisome proliferator activated receptor-γagonist troglitazone protects against nondiabetic glomerulosclerosis in rats.Kidney Int,2001,59:1899-1910.
18.Kumar D.Zimpelmann J,Robertson S,et a1.Tubular and interstitial cell apoptosis in the streptozotocin-diabetic rat kidney[J].Nephron Exp Nephrol,2004,96(3):e77一e88
19.张艳玲,段惠军,李春香,等.糖尿病大鼠肾脏细胞凋亡与Bax和Bcl一2基因表达[J].中国糖尿病杂志,2002,10(3):159-162.
20.王先令,陆菊明.血糖波动对糖尿病预后及其慢性并发症发生发展的影响[J].国外医学:内分泌学分册,2005,25(3):169-173
21.Guan Y,Zhang Y,Schneider A,et a1.Peroxisome proliferators_activated receptor-gamma activeity is associated with renal microvasculature [J].Am J Physiol Renal Physiol,2001,281(6):F1036-F1046
22.Saltiel AR,Olefsky JM.ThiazoIidinediones in the treatment of insulin resistance and type II diabetes.Diabetes,1996,45(12):1661-1669.
23.李延兵,廖志红,黄知敏,等.吡格列酮和二甲双胍对2型糖尿病胰岛素抵抗的影响.中华内分泌代谢杂志,2004,20(1):30—32
24.余叶蓉,李延兵,樊继援,等.吡格列酮与二甲双胍治疗2型糖尿病的疗效比较.中华内分泌代谢杂志,2003,19(3):232-234.
25.Shichiri M, Kishikawa H, Ohkubo Y, et al. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabeticpatients [ J] . Diabetes Care, 2000, 23( Suppl 2) : B21- B29.
26.孙子林,任晓妹,金晖,等。余叶蓉吡格列酮对2型糖尿病肾病患者血清AGE-肽和MCP-1的影响。江苏医药,2006,32(2):101-103。
27 .Martens FM ,Visseren FL,Lemay J,et a1.Metabolic and additional vascular effects of thiazolidinediones.Drugs,2002,62:1463-1480.
28 .Goldberg RB, Kendall DM, Deeg MA,et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005 Jul;28(7):1547-54.
29. Paffen E,Demaat M P.C-reactive protein in atherosclerosis:A causal factor?[J].Cardio-Vasc Res,2006,71(1):30-9.
30 .Singh U,Devaraj S,Jialal I,et a1.C-reactive protein decreases tissue plasminogen activator activity in human aortic endothelial cells evidence that C-reactive protein is a procoagula[J].Arterioscler Thromb Vasc Boil,2005,25(10):2216-21.
31. Verma S,Li S H,Badiwala M V,et a1.Endothelin antagonism and Interleukin-6 inhibition attenuate the proatherogenic effects of C.reactive protein[J].Circulation,2002,105(16):1890-6.
32.廖岚,雷闽湘,陈慧玲,等,高敏c-反应蛋白与2型糖尿病肾病[J].中南大学学报(医学版),2004,29(6):627-30
33.Stehouwer C D,Gall M A,Twisk J W,et al,Increased urinary a1bumin excretion,endothelial dysfunction and chronic low-grade inflammation in type 2 diab etes:Progressive,interrelated,and independently associated with risk of death[J] Diabetes,2002,51(4):1157-65
34. Zheng F,Fomoni A,Elliot SJ,et a1.Upregulation of type I collagen by TGF-beta in mesangial cells is blocked by PPARgamma activation.Am J Physiol Renal Physiol,2002.282:F639一F648.
35.孙海艳,屈会起,邱明才.吡格列酮对链脲佐菌素诱导的糖尿病大鼠肾脏保护作用研究.中华内科杂志,2003,42(8):579-580.
36.阮昱,李红,郑芬萍,等.吡格列酮对糖尿病大鼠肾脏转化生长因子β1及Ⅳ型胶原表达的作用.中华糖尿病杂志,2004,12(5):373-376.
37.董凤芹,李红,蔡卫民,等.吡格列酮对糖尿病大鼠肾组织基质金属蛋白酶2和9表达的影响.中华内分泌代谢杂志,2004,20(5):459-460。
38. McLennan SV, Yue DK, Turtle JR,et al. Effect of glucose on matrix metalloproteinase activity in mesangial cells. Nephron. 1998;79(3):293-8.
39. McLennan SV, Martell SY, Yue DK,et al. High glucose concentration inhibits the expression of membrane type metalloproteinase by mesangial cells: possible role in mesangium accumulation. Diabetologia. 2000 May;43(5):642-8.
40. Lupia E, Elliot SJ, Lenz O,et al. IGF-1 decreases collagen degradation in diabetic NOD mesangial cells: implications for diabetic nephropathy. Diabetes. 1999 Aug;48(8):1638-44.
41. Nicholas SB, Kawano Y, Wakino S,et al. Expression and function of peroxisome proliferator-activated receptor-gamma in mesangial cells. Hypertension. 2001 Feb;37(2 Part 2):722-727.
42.Zilin S ,Naifeng L ,Bicheng L ,et al . The determination of AGE-peptides by flow injection assay , a practical marker of diabetic nephropathy. Clin Chim Acta ,2001 ,313 :69-75.
43.Nakamura T ,Matsuda T , Kawagoe Y,et al . Effect of pioglitazone on carotid intima-media thickness and arterial stiffness in type 2 diabetic nephropathy patients. Metabolism , 2004 , 53 :1382-1386.
44.Parulkar A,Pendergrass ML,Granda-Ayala。et a1.Nonhypoglycemic effects of thiazolidinediones [J].Ann Intern Med.2001,134(1):61-67.
45.Pistrosch F,Pssauer J,Fischer S,et a1.In type 2 diabetes,rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control[J].Diabetes Care,2004,27(2):484-490.
46.Natali A,Baldeweg S,Tosehi E,et a1.Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes[J].Diabetes Care,2004。27(6):1349-1357.
47.Boyle PJ,King AB,Olansky L,et a1.Effects of pioglitazone and rosiglitazoneon blood lipid levels and glycemie control in patients with type 2 diabetes mllitus:a retrospective review of randomly selected medical records[J].Clin Ther,2002.24(3):378-396
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |