舒洛地特对糖尿病肾脏的保护作用及其机制探讨
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摘要
目的
观察舒洛地特对已应用ACEI和/或ARB类药物的2型糖尿病肾病患者的临床疗效及安全性。
方法
根据尿白蛋白排泄率将92例2型糖尿病肾病患者分为微量白蛋白尿组和大量白蛋白尿组，所有患者在入组前至少服用一种ACEI或ARB类降压药6个月，入组后在常规综合治疗的同时，前10天应用舒洛地特注射剂60mg/d静滴，后110天应用舒洛地特软胶囊100mg/d口服。用药前、用药4周、8周、12周及120天分别检测患者血压、空腹血糖、肝肾功能、凝血功能、24h尿蛋白定量等指标，并观察有无不良事件发生。
结果
微量白蛋白组和大量白蛋白组患者24h尿蛋白定量在治疗前分别为（0.62±0.13）g和（4.86±0.92）g，治疗12周后分别为（0.40±0.11）g和（3.02±0.73）g，治疗前后比较差异均有统计学意义（P<0.05）；治疗120天后两组患者24h尿蛋白定量分别为（0.36±0.12）g和（2.73±0.82）g，同治疗前比较分别下降（38.97±14.67）%和（41.32±18.24）%，两组患者下降率比较无统计学差异（P>0.05）。两组患者治疗前后血压、血糖、肝肾功能、凝血功能等指标均未见显著变化。治疗过程中所有患者均无严重不良反应发生。
结论
对已应用ACEI和/或ARB的伴有微量白蛋白尿或大量白蛋白尿的2型DN患者，舒洛地特能有效降低其尿蛋白，短期内对肝肾功能、凝血功能等指标无明显影响，临床应用安全。
目的
观察舒洛地特对糖尿病大鼠肾脏的保护作用并探讨其机制。
方法
采用STZ（链脲佐霉素，60mg/kg）腹腔注射法构建1型糖尿病大鼠模型，随机分为4组：DM组（糖尿病组）、S10组（舒洛地特10mg/kg/d组）、S20组（舒洛地特20mg/kg/d组）、L组（氯沙坦30mg/kg/d组），每组各10只。另取10只未造模大鼠作N组（正常对照组）。干预12周后采集各组大鼠血、尿标本和肾脏组织标本，观察和分析各组大鼠肾脏功能和结构的改变；Western blotting和免疫组织化学法检测肾组织VEGF、VEGF-R2、SOCS-1及TGF-β1蛋白的表达。
结果
同N组相比，DM组大鼠24h尿白蛋白定量、血肌酐及尿素氮显著增加（P<0.01），病理改变较明显。同DM组相比，治疗组（S10、S20及L组）大鼠24h尿白蛋白定量减少（P<0.05或P<0.01）；同S10组相比，S20及L组大鼠24h尿白蛋白定量减少（P<0.05）。光镜及电镜显示治疗组较DM组病理变化减轻，尤以S20及L组病变减轻明显。大鼠肾脏组织VEGF和VEGF-R2的表达，DM组明显高于N组（P<0.01），治疗组显著低于DM组（P<0.05或P<0.01）；SOCS-1的表达，DM组明显高于N组（P<0.05），治疗组显著高于DM组（P<0.05或P<0.01），而TGF-β1的表达，DM组明显高于N组（P<0.01），治疗组显著低于DM组（P<0.05或P<0.01）。
结论
舒洛地特对糖尿病大鼠肾脏有保护作用，而20mg/kg/d较10mg/kg/d的剂量效果更好。这种保护作用可能同下调肾脏组织VEGF和VEGF-R2蛋白表达，以及上调肾脏组织SOCS-1蛋白的表达，进而抑制TGF-β1蛋白的过表达有关。
Objective
To observe the efficacy and safety of sulodexide on patients of type2diabeticnephropathy who have received ACEI and/or ARB therapy.
Methods
A total of92cases of type2diabetic nephropathy patients, who had received at leastone kind of ACEI and/or ARB drug therapy for at least6months, were devided into twogroups: the microalbuminuria group and the macroalbuminuria group. All the patients weregiven sulodexide60mg/d by intravenous infusion for10days, and then given sulodexide100mg/d by oral use for110days besides routine management. The blood pressure, fastingblood glucose, liver and kidney function, blood coagulation and24-hour urinary proteinwere measured before and4weeks,8weeks,12weeks and120days after the use ofsulodexide.
Results
The24-hour urinary protein of the microalbuminuria group and the macroalbuminuriagroup were (0.62±0.13)g and (4.86±0.92)g before the treatment. And12weeks later, the24-hour urinary protein were （0.40±0.11）g and （3.02±0.73）g respectively. Thedifferences of the24-hour urinary protein before and after the treatment both of the groupswere significant（P<0.05）.120days of the treatment later, the24-hour urinary protein ofthe two groups were （0.36±0.12）g and （2.73±0.82）g, and reduced （38.97±14.67）%and （41.32±18.24）%respectively compared to those before the treatment. There wasno significant difference of the rate of the decline between the two groups（P>0.05）. There were no significant differences of the blood pressure, blood glucose, blood coagulation,liver and kidney function before and after the treatment both of the groups. There were noserious adverse events occurred during the treatment.
Conclusions
Sulodexide can effectively reduce urinary protein of type2DN patients withmicroalbuminuria or macroalbuminuria who have received ACEI and/or ARB therapy. Ithad no significant effect on the blood pressure, blood glucose, blood coagulation, liver andkidney function in short term. And it’s safe in clinical application.
Objective
To observe the renal protection of sulodexide in diabetic rats and to investigate themechanism.
Methods
The rat models of type1diabetes were established by intraperitoneal injection of STZ(streptozotocin,60mg/kg). Then the rats were randomly devided into four groups: DMgroup (diabetic model group), S10group (10mg/kg/d sulodexide group), S20group(20mg/kg/d sulodexide group), L group (losartan30mg/kg/d group),10rats per group.Another10normal rats were used as N group (normal control group). All the rats weretreated for12weaks. Then body weight,24-hour urinary albumin excretion, blood glucose(BG),serum creatinine(Scr), blood urea nitrogen(BUN) and kidney weight were measured;renal tissue samples were observed under optical and electron microscope. Expressions ofVEGF, VEGF receptor2(VEGF-R2), SOCS1and TGF-β1in renal tissue samples weredetected by Western blotting and immunohistochemistry.
Results
Compared with N group, DM group had significantly higher24-hour urinary albuminexcretion, Scr and BUN (P＜0.01), the pathological changes in the renal tissue samples inDM group were also obvious. Compared with DM group, the treated groups (S10, S20, and L group) had significantly lower24-hour urinary albumin excretion（P<0.05or P<0.01）,but there were no significant differences of Scr and BUN among the treated groups andDM group（P>0.05）. Compared with S10group, S20and L group had significantly lower24-hour urinary albumin excretion（P<0.05）. The pathological changes in the renal tissuesamples were much ameliorated in the treated groups, especially those in the S20and Lgroup. The expressions of VEGF and VEGF-R2in DM group were significantly higherthan those in N group （P<0.01）, and the expressions in the treated groups weresignificantly lower than that in DM group（P<0.05or P<0.01）. The expression of SOCS1in DM group was significantly higher than that in N group （P<0.05）, and the expressionin the treated groups was much higher than that in DM group （P<0.05or P<0.01）. Theexpression of TGF-β1in DM group was significantly higher than that in N group（P<0.01）,and the expression in the treated groups was significantly lower than that in DM group（P<0.05or P<0.01）.
Conclusions
Sulodexide has renal protective effect in diabetic rats, and20mg/kg/d is moreeffective than10mg/kg/d. The nephroprotective effect may be related to the regulating ofthe expressions of VEGF, VEGF-R2, SOCS1and TGF-β1in the renal tissues of diabeticrats.
观察舒洛地特对已应用ACEI和/或ARB类药物的2型糖尿病肾病患者的临床疗效及安全性。
方法
根据尿白蛋白排泄率将92例2型糖尿病肾病患者分为微量白蛋白尿组和大量白蛋白尿组，所有患者在入组前至少服用一种ACEI或ARB类降压药6个月，入组后在常规综合治疗的同时，前10天应用舒洛地特注射剂60mg/d静滴，后110天应用舒洛地特软胶囊100mg/d口服。用药前、用药4周、8周、12周及120天分别检测患者血压、空腹血糖、肝肾功能、凝血功能、24h尿蛋白定量等指标，并观察有无不良事件发生。
结果
微量白蛋白组和大量白蛋白组患者24h尿蛋白定量在治疗前分别为（0.62±0.13）g和（4.86±0.92）g，治疗12周后分别为（0.40±0.11）g和（3.02±0.73）g，治疗前后比较差异均有统计学意义（P<0.05）；治疗120天后两组患者24h尿蛋白定量分别为（0.36±0.12）g和（2.73±0.82）g，同治疗前比较分别下降（38.97±14.67）%和（41.32±18.24）%，两组患者下降率比较无统计学差异（P>0.05）。两组患者治疗前后血压、血糖、肝肾功能、凝血功能等指标均未见显著变化。治疗过程中所有患者均无严重不良反应发生。
结论
对已应用ACEI和/或ARB的伴有微量白蛋白尿或大量白蛋白尿的2型DN患者，舒洛地特能有效降低其尿蛋白，短期内对肝肾功能、凝血功能等指标无明显影响，临床应用安全。
目的
观察舒洛地特对糖尿病大鼠肾脏的保护作用并探讨其机制。
方法
采用STZ（链脲佐霉素，60mg/kg）腹腔注射法构建1型糖尿病大鼠模型，随机分为4组：DM组（糖尿病组）、S10组（舒洛地特10mg/kg/d组）、S20组（舒洛地特20mg/kg/d组）、L组（氯沙坦30mg/kg/d组），每组各10只。另取10只未造模大鼠作N组（正常对照组）。干预12周后采集各组大鼠血、尿标本和肾脏组织标本，观察和分析各组大鼠肾脏功能和结构的改变；Western blotting和免疫组织化学法检测肾组织VEGF、VEGF-R2、SOCS-1及TGF-β1蛋白的表达。
结果
同N组相比，DM组大鼠24h尿白蛋白定量、血肌酐及尿素氮显著增加（P<0.01），病理改变较明显。同DM组相比，治疗组（S10、S20及L组）大鼠24h尿白蛋白定量减少（P<0.05或P<0.01）；同S10组相比，S20及L组大鼠24h尿白蛋白定量减少（P<0.05）。光镜及电镜显示治疗组较DM组病理变化减轻，尤以S20及L组病变减轻明显。大鼠肾脏组织VEGF和VEGF-R2的表达，DM组明显高于N组（P<0.01），治疗组显著低于DM组（P<0.05或P<0.01）；SOCS-1的表达，DM组明显高于N组（P<0.05），治疗组显著高于DM组（P<0.05或P<0.01），而TGF-β1的表达，DM组明显高于N组（P<0.01），治疗组显著低于DM组（P<0.05或P<0.01）。
结论
舒洛地特对糖尿病大鼠肾脏有保护作用，而20mg/kg/d较10mg/kg/d的剂量效果更好。这种保护作用可能同下调肾脏组织VEGF和VEGF-R2蛋白表达，以及上调肾脏组织SOCS-1蛋白的表达，进而抑制TGF-β1蛋白的过表达有关。
Objective
To observe the efficacy and safety of sulodexide on patients of type2diabeticnephropathy who have received ACEI and/or ARB therapy.
Methods
A total of92cases of type2diabetic nephropathy patients, who had received at leastone kind of ACEI and/or ARB drug therapy for at least6months, were devided into twogroups: the microalbuminuria group and the macroalbuminuria group. All the patients weregiven sulodexide60mg/d by intravenous infusion for10days, and then given sulodexide100mg/d by oral use for110days besides routine management. The blood pressure, fastingblood glucose, liver and kidney function, blood coagulation and24-hour urinary proteinwere measured before and4weeks,8weeks,12weeks and120days after the use ofsulodexide.
Results
The24-hour urinary protein of the microalbuminuria group and the macroalbuminuriagroup were (0.62±0.13)g and (4.86±0.92)g before the treatment. And12weeks later, the24-hour urinary protein were （0.40±0.11）g and （3.02±0.73）g respectively. Thedifferences of the24-hour urinary protein before and after the treatment both of the groupswere significant（P<0.05）.120days of the treatment later, the24-hour urinary protein ofthe two groups were （0.36±0.12）g and （2.73±0.82）g, and reduced （38.97±14.67）%and （41.32±18.24）%respectively compared to those before the treatment. There wasno significant difference of the rate of the decline between the two groups（P>0.05）. There were no significant differences of the blood pressure, blood glucose, blood coagulation,liver and kidney function before and after the treatment both of the groups. There were noserious adverse events occurred during the treatment.
Conclusions
Sulodexide can effectively reduce urinary protein of type2DN patients withmicroalbuminuria or macroalbuminuria who have received ACEI and/or ARB therapy. Ithad no significant effect on the blood pressure, blood glucose, blood coagulation, liver andkidney function in short term. And it’s safe in clinical application.
Objective
To observe the renal protection of sulodexide in diabetic rats and to investigate themechanism.
Methods
The rat models of type1diabetes were established by intraperitoneal injection of STZ(streptozotocin,60mg/kg). Then the rats were randomly devided into four groups: DMgroup (diabetic model group), S10group (10mg/kg/d sulodexide group), S20group(20mg/kg/d sulodexide group), L group (losartan30mg/kg/d group),10rats per group.Another10normal rats were used as N group (normal control group). All the rats weretreated for12weaks. Then body weight,24-hour urinary albumin excretion, blood glucose(BG),serum creatinine(Scr), blood urea nitrogen(BUN) and kidney weight were measured;renal tissue samples were observed under optical and electron microscope. Expressions ofVEGF, VEGF receptor2(VEGF-R2), SOCS1and TGF-β1in renal tissue samples weredetected by Western blotting and immunohistochemistry.
Results
Compared with N group, DM group had significantly higher24-hour urinary albuminexcretion, Scr and BUN (P＜0.01), the pathological changes in the renal tissue samples inDM group were also obvious. Compared with DM group, the treated groups (S10, S20, and L group) had significantly lower24-hour urinary albumin excretion（P<0.05or P<0.01）,but there were no significant differences of Scr and BUN among the treated groups andDM group（P>0.05）. Compared with S10group, S20and L group had significantly lower24-hour urinary albumin excretion（P<0.05）. The pathological changes in the renal tissuesamples were much ameliorated in the treated groups, especially those in the S20and Lgroup. The expressions of VEGF and VEGF-R2in DM group were significantly higherthan those in N group （P<0.01）, and the expressions in the treated groups weresignificantly lower than that in DM group（P<0.05or P<0.01）. The expression of SOCS1in DM group was significantly higher than that in N group （P<0.05）, and the expressionin the treated groups was much higher than that in DM group （P<0.05or P<0.01）. Theexpression of TGF-β1in DM group was significantly higher than that in N group（P<0.01）,and the expression in the treated groups was significantly lower than that in DM group（P<0.05or P<0.01）.
Conclusions
Sulodexide has renal protective effect in diabetic rats, and20mg/kg/d is moreeffective than10mg/kg/d. The nephroprotective effect may be related to the regulating ofthe expressions of VEGF, VEGF-R2, SOCS1and TGF-β1in the renal tissues of diabeticrats.
引文
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3. Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria inmicroalbuminuric and macroalbuminuric type1and type2diabetic patients: the Di.N.A.S. randomized trial[J]. J Am Soc Nephrol,2002,13(6):1615-1625.
4. Heerspink HL, Greene T, Lewis JB, et al. Effects of sulodexide in patients with type2diabetes and persistent albuminuria[J]. Nephrol Dial Transplant,2008,23(6):1946-1954.
5. Blouza S, Dakhli S, Abid H, et al. Efficacy of low-dose oral sulodexide in themanagement of diabetic nephropathy[J]. J Nephrol,2010,23(4):415-424.
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1. Lewis EJ, Lexis JB, Greene T, et al. Sulodexide for Kidney Protection in Type2Diabetes Patients With Microalbuminuria: A Randomized Controlled Trial [J].Am JKidney Dis,2011,58(5):729-736.
2. Rossini M,Naito T,Yanq H,et al. Sulodexide ameliorates early but not late kidneydisease in models of radiation nephropathy and diabetic nephropathy [J].Nephrol DialTransplant,2010,25(6):1803-1810.
3. Harenberg J.Review of pharmacodynamics,pharmacokinetics,and therapeuticproperties of sulodexide[J].Med Res Rev,1998,18(1):1-20.
4. Solini A,Carraro A,Barzon I,et a1.Therapy with glycosaminoglycans lowers albuminexcretion in non—insulin dependent diabetic patients withmicroalbuminuria[J],Diabetes Nutr Metab,1994,7:304-307.
5. Mogensen CE.Renal function changes in diabetes[J]. Diabetes,1976,25(Suppl):872-879.
6. de Zeeuw D,Remuzzi G,Parving HH,et al.Albuminuria,a therapeutic target forcardiovascular protection in type2diabetic patients withnephropathy[J].2004,110(8):921-927.
7. Broekhuizen LN,Lemkes BA,Mooij HL,et al.Effect of sulodexide on endothelialglycocalyx and vascular permeability in patients with type2diabetesmellitus[J].Diabetologia,2010,53(12):2646–2655.
8. Xu X,Rao G,Maxhimer JB.Mechanism of action of sulodexide-mediated control ofdiabetic proteinuria: inhibition of heparanase-1activity[J].Am SocNephrol,2005,16(4):673A.
9. Mcnica C,Giovanni G,Ulrich S,et al.Glycosaminoglycan therapy prevents TGF-β1overexpression and pathologic changes in renal tissue of long-term diabetic rats[J].AmSoc Nephrol,2000,11:2324–2336.
10. Shan CHEN,Zhan FANG,Zhonghua ZHU,et al.Protective Effect of Sulodexide onPodocyte Injury in Adriamycin nephropathy Rats[J].Huazhong Univ SciTechnol,2009,29(6):715-719．
11.舒冏，曾龙驿，王曼曼，等．舒洛地特对大鼠糖尿病肾脏的保护作用及其机制[J]．中国医院药学杂志，2009，29(1)：19-23．
12. Ciszewicz M,Polubinska A,Antoniewicz A,et al.Sulodexide suppresses inflammation inhuman endothelial cells and prevents glucose cytotoxicity[J].TranslRes,2009,153(3):118–123.
13. Gambaro G,Kinalska I,Oksa A,et al.Oral sulodexide reduces albuminuria inmicroalbuminuric and macroalbuminuric type1and type2diabetic patients:theDi.N.A.S.randomized trial. J Am Soc Nepphrol,2002,13(6):1615-1625.
14.张自沛．药理学实验．第二版．北京：人民卫生出版社，1996：238．
1. Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria inmicroalbuminuric and macroalbuminuric type1and type2diabetic patients: the Di.N.A.S. randomized trial[J]. J Am Soc Nephrol,2002,13(6):1615-1625.
2. Heerspink HL, Greene T, Lewis JB, et al. Effects of sulodexide in patients with type2diabetes and persistent albuminuria[J]. Nephrol Dial Transplant,2008,23(6):1946-1954.
3. Blouza S, Dakhli S, Abid H, et al. Efficacy of low-dose oral sulodexide in themanagement of diabetic nephropathy[J]. J Nephrol,2010,23(4):415-424.
4. Gu K, Zhao JD, Ren ZG, et al. A natural process of cirrhosis resolution anddeceleration of liver regeneration after thioacetamide withdrawal in a rat model[J]. MolBiol Rep,2011,38(3):1687-1696.
5. de Zeeuw D,Remuzzi G,Parving HH,et al.Albuminuria,a therapeutic target forcardiovascular protection in type2diabetic patients with nephropathy[J].2004,110(8):921-927.
6. Cooper ME, Vranes D, Yonssef S, et a1. Increased renal expression of vascularendothelial growth factor and its receptor VEGFR-2in experimental diabetes[J].Diabetes,1999,8(11):2229-2239.
7. Liu E, Morimoto M, Kitajima S, et a1. Increased Expression of Vascular EndothelialGrowth Factor in Kidney Leads to Progressive Impairment of Glomerular Functions[J].J Am Soc Nephrol,2007,18(7):2094–2104.
8. Veron D, Reidy KJ, Bertuccio C, et al. Overexpression of VEGF-A in podocytes ofadult mice causes glomerular disease[J]. Kidney International,2010,77(11):989–999.
9. Chen S, Ziyadeh FN. Vascular Endothelial Growth Factor and Diabetic Nephropathy[J].Current Diabetes Reports,2008,8(6):470–476.
10. Bates DO. Vascular endothelial growth factors and vascular permeability[J].Cardiovascular Research,2010,87(2):262–271.
11. Zeng L, Xu H, Chew TL, et al. HMG CoA reductase inhibition modulatesVEGF-induced endothelial cell hyperpermeability by preventing RhoA activation andmyosin regulatory light chain phosphorylation[J]. FASEB J,2005,19(13):1845–1847.
12. Chen S, Kasama Y, Lee JS, et al. Podocyte-derived vascular endothelial growth factormediates the stimulation of α3(IV)collagen production by transforming growthfactor-β1in mouse podocytes[J]. Diabetes,2004,53(1):2939–2949.
13. Sung SH, Ziyadeh FN, Wang A, et al. Blockade of vascular endothelial growth factorsignaling ameliorates diabetic albuminuria in mice[J]. J Am Soc Nephrol,2006,17(11):3093–3104.
14.孙昭，胡宗兰，丁晓红，等．低分子肝素对肿瘤细胞分泌血管内皮生长因子的影响[J]．中华肿瘤杂志，2009；31（11）：826-830．
15.甘良英，于仲元，蔡美顺，等．低分子质量肝素对糖尿病肾病大鼠肾血管内皮生长因子表达的影响[J]．北京大学学报（医学版），2005；37（4）：382-385．
16.顾红卫，倪兆慧，顾乐怡，等．血管生成素在糖尿病大鼠肾组织中的表达及氯沙坦的作用[J]．中国血液净化，2010；9（1）：32-36．
17. Kitamura S, Maeshima Y, Sugaya T, et al. Transforming growth factor-beta1inducesvascular endothelial growth factor expression in murine proximal tubular epithelialcells[J]. Nephron Exp Nephrol,2003,95(2):79-86.
18.林可意，曾龙驿，舒冏，等．舒洛地特对糖尿病大鼠尿白蛋白排泄率及肾脏转化生长因子-β1表达的影响[J]．中华糖尿病杂志，2009，1（3）：196-200．
19.张自沛．药理学实验(M)．第二版．北京：人民卫生出版社，1996：238．
1. Marrero MB, Banes-Berceli AK, Sten DM, et al. Role of the JAK/STAT signalingpathway in diabetic nephropathy. Am J Physiol Renal Physilol,2006,290(4):F762-F768.
2. Brosius FC, Ⅲ: New insights into the mechanisms of fibrosis and sclerosis in diabeticnephropathy. Rev Endocr Metab Disord,9(4):245-254.
3. Wanq X, Shaw S, Amiri F, et al. Inhibition of the JAK/STAT signaling pathwayprevents the high glucose-induced increase in tgf-beta and fibronectin synthesis inmesangial cells. Diabetes,51(12):3505-3509.
4. Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria inmicroalbuminuric and macroalbuminuric type1and type2diabetic patients: the Di.N.A.S. randomized trial[J]. J Am Soc Nephrol,2002,13(6):1615-1625.
5. Heerspink HL, Greene T, Lewis JB, et al. Effects of sulodexide in patients with type2diabetes and persistent albuminuria[J]. Nephrol Dial Transplant,2008,23(6):1946-1954.
6. Blouza S, Dakhli S, Abid H, et al. Efficacy of low-dose oral sulodexide in themanagement of diabetic nephropathy[J]. J Nephrol,2010,23(4):415-424.
7. Gu K, Zhao JD, Ren ZG, et al. A natural process of cirrhosis resolution anddeceleration of liver regeneration after thioacetamide withdrawal in a rat model[J]. MolBiol Rep,2011,38(3):1687-1696.
8. Duronio V, Scheid MP, Ettinger S. Downstream signalling events regulated byphosphatidylinositol3-kinase activity. Cell Signal,1998,10(4):233-239.
9. Kubo M, Hanada T, Yoshimura A. Suppressors of cytokine signaling and immunity.
10. Ortiz MG, Lopez PV, Lopez FO, et al. Suppressors of cytokine signaling abrogatediabetic nephropathy. J Am Soc Nephrol,2010,21(5):763-772.
11. Shi Y, Zhanq Y, Wanq C, et al. Suppressor of cytokine signaling-1reduces highglucose-induced TGF-beta1and fibronectin synthesis in human mesangial cells. FEBSLett,2008,582(23-24):3484-3488.
12. Shi Y, Du C, Zhanq Y, et al. Suppressor of cytokine signaling-1ameliorates expressionof MCP-1in diabetic nephropathy.2010,31(5):380-388.
1. Harenberg J,Review of pharmacodynamics,pharmacokinetics,and therapeutic propertiesof sulodexide[J].Med Res Rev,1998,18(1):1-20.
2. Solini A,Carraro A,Barzon I,et a1.Therapy with glycosaminoglycans lowers albuminexcretion in non—insulin dependent diabetic patients withmicroalbuminuria[J],Diabetes Nutr Metab,1994,7:304-307.
3. Ram Weiss,Robert Niecestro,Itamar Raz,The Role of Sulodexide in the Treatment ofDiabetic Nephropathy[J].Drugs,2007,67(18):2681-2696.
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8. Gambaro G, Ceol M, Antonello A. The Steno hypothesis for cardiovascular and renaldisease revisited. In: Mogensen CE, editor.The kidney and hypertension in diabetesmellitus.6th ed.Boston (MA): Kluwer Academic Publishers,2003:27-43.
9. Broekhuizen LN,Lemkes BA,Mooij HL,et al.Effect of sulodexide on endothelialglycocalyx and vascular permeability in patients with type2diabetesmellitus[J].Diabetologia,2010,53(12):2646–2655.
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15. Xu X,Rao G,Maxhimer JB.Mechanism of action of sulodexide-mediated control ofdiabetic proteinuria: inhibition of heparanase-1activity[J].Am SocNephrol,2005,16(4):673A.
16.梁伟，余碧影，丁国华，等．舒洛地特对糖尿病高血压大鼠足细胞podocalyxin表达的影响[J]．中华肾脏病杂志，2009，25(7)：497-502．
17. Shan CHEN,Zhan FANG,Zhonghua ZHU,et al.Protective Effect of Sulodexide onPodocyte Injury in Adriamycin nephropathy Rats[J].Huazhong Univ SciTechnol,2009,29(6):715-719．
18. Ishikawa Y,Kitamura M.Inhibition of glomerular cell apoptosis by heparin[J].KidneyInt,1999,56(3):954-63．
19.舒冏，曾龙驿，王曼曼，等．舒洛地特对大鼠糖尿病肾脏的保护作用及其其机制[J]．中国医院药学杂志，2009，29(1)：19-23．
20. Ciszewicz M,Polubinska A,Antoniewicz A,et al.Sulodexide suppresses inflammation inhuman endothelial cells and prevents glucose cytotoxicity[J].TranslRes,2009,153(3):118–123.
21.胡凤琪，丁国华，梁伟，等．舒洛地特对糖尿病高血压大鼠肾脏单核细胞趋化蛋白-1表达的影响[J]．临床肾脏病杂志，2010；10（4）：178-180．
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23. Femiano F,Gombos F,Scully C.Recurrent aphthous stomatitis unresponsive to topicalcorticosteroids:a study of the comparative therapeutic effects of systemic prednisoneand systemic sulodexide[J].Int J Dermatol,2003,42(5):394-397.
24..Lauver D A,Lucehesi B R,Sulodexide:a renewed interest in thisglycosaminoglycan[J].Cardlovasc Drug Bey,2006,24(3-4):214-226.
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26.曾龙驿，林可意，舒冏，等．舒洛地特对糖尿病大鼠肾脏结构及功能的影响[J]．解放军医学杂志，2009，34(1)：69-71．
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30. Mizutani K,Kawashima S,Ueyama T,et al.Heparin and heparan sulfate inhibitextracellular signal-regulated kinase activation and myocardial cell hypertrophyinduced by endothelin-1[J].Kobe J Med Sci,2001,47(2):47-58.
31.林可意，曾龙驿，舒冏，等．舒洛地特对糖尿病大鼠尿白蛋白排泄率及肾脏转化生长因子-β1表达的影响[J]．中华糖尿病杂志，2009，1（3）：196-200．
32. Mcnica C,Giovanni G,Ulrich S,et al.Glycosaminoglycan therapy prevents TGF-β1overexpression and pathologic changes in renal tissue of long-term diabeticrats[J].Am Soc Nephrol,2000,11:2324–2336.
33.徐海平,郑红光．舒洛地特对糖尿病大鼠的肾脏保护作用[J]．沈阳部队医药，2009，22（3）：172-176．
34. Mandal A K,Lyden T W,Saklayen M G.Heparin lowers blood pressure:biological andclinical perspectives[J]．Kidney Int.1995,47:1017—1022．
35.郭红，甘良英，于仲元，等．低分子肝素对糖尿病大鼠早期肾脏病变的防护作用[J]．中华医学杂志，2001，81(21)：132．
36. Radhakrishnamurthy B,Sharma C,Bhandaru RR et al.Studies of chemical and biologicproperties of a fraction of sulodexide, a heparin-like glycosaminoglycan[J].Atherosclerosis,1986,60:141–149.
37. Jacek B,Miroslaw D,Krysyna P,et al.Sulodexide induces hepatocyte growth factorrelease in humans[J]. European Journal of Pharmacology,2007,558:167–171.
○1上海交通大学附属第六人民医院肾内科（上海200233）
2. Solini A,Carraro A,Barzon I,et a1.Therapy with glycosaminoglycans lowers albuminexcretion in non—insulin dependent diabetic patients withmicroalbuminuria[J],Diabetes Nutr Metab,1994,7:304-307.
3. Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria inmicroalbuminuric and macroalbuminuric type1and type2diabetic patients: the Di.N.A.S. randomized trial[J]. J Am Soc Nephrol,2002,13(6):1615-1625.
4. Heerspink HL, Greene T, Lewis JB, et al. Effects of sulodexide in patients with type2diabetes and persistent albuminuria[J]. Nephrol Dial Transplant,2008,23(6):1946-1954.
5. Blouza S, Dakhli S, Abid H, et al. Efficacy of low-dose oral sulodexide in themanagement of diabetic nephropathy[J]. J Nephrol,2010,23(4):415-424.
6. Lewis EJ, Lexis JB, Greene T, et al. Sulodexide for Kidney Protection in Type2Diabetes Patients With Microalbuminuria: A Randomized Controlled Trial [J].Am JKidney Dis,2011,58(5):729-736.
7. Packham DK, Wolfe R, Reutens AT, et al. Sulodexide fails to demonstraterenoprotection in overt type2diabetic nephropathy[J]. J Am Soc Nephrol,2012,23(1):123-130.
8. Mogensen CE.Renal function changes in diabetes[J]. Diabetes,1976,25(Suppl):872-879.
9. de Zeeuw D,Remuzzi G,Parving HH, et al. Albuminuria,a therapeutic target forcardiovascular protection in type2diabetic patients with nephropathy[J].2004,110(8):921-927.
10. Harenberg J,Review of pharmacodynamics,pharmacokinetics, and therapeuticproperties of sulodexide[J]. Med Res Rev,1998,18(1):1-20.
11. Gambaro G, Ceol M, Antonello A. The Steno hypothesis for cardiovascular and renaldisease revisited. In: Mogensen CE, editor.The kidney and hypertension in diabetesmellitus.6th ed. Boston (MA): Kluwer Academic Publishers,2003:27-43.
12.Broekhuizen LN, Lemkes BA, Mooij HL, et al. Effect of sulodexide on endothelialglycocalyx and vascular permeability in patients with type2diabetes mellitus[J].Diabetologia,2010,53(12):2646–2655.
13. M J van den Hoven,A L Rops, M A Bakker, J Aten,et al. Increased expression ofheparanase in overt diabetic nephropathy Heparanase expression in diabeticnephropathy[J]. Kidney International,2006,70:2100-2108.
14. Xu X, Rao G,Maxhimer JB. Mechanism of action of sulodexide-mediated control ofdiabetic proteinuria: inhibition of heparanase-1activity[J]. Am Soc Nephrol,2005,16(4):673A.
15.梁伟，余碧影，丁国华，等．舒洛地特对糖尿病高血压大鼠足细胞podocalyxin表达的影响[J]．中华肾脏病杂志，2009，25(7)：497-502．
16. Shan CHEN, Zhan FANG, Zhonghua ZHU, et al. Protective Effect of Sulodexide onPodocyte Injury in Adriamycin nephropathy Rats[J]. Huazhong Univ Sci Technol,2009,29(6):715-719.
17.林可意，曾龙驿，舒冏，等．舒洛地特对糖尿病大鼠尿白蛋白排泄率及肾脏转化生长因子-β1表达的影响[J]．中华糖尿病杂志，2009，1（3）：196-200．
18. Ofosu FA. Pharmacological actions of sulodexide[J]. Semin Thromb Hemost,1998,24(2):127-138.
19. Radhakrishnamurthy B,Sharma C,Bhandaru RR et al.Studies of chemical and biologicproperties of a fraction of sulodexide, a heparin-like glycosaminoglycan[J].Atherosclerosis,1986,60:141–149.
1. Lewis EJ, Lexis JB, Greene T, et al. Sulodexide for Kidney Protection in Type2Diabetes Patients With Microalbuminuria: A Randomized Controlled Trial [J].Am JKidney Dis,2011,58(5):729-736.
2. Rossini M,Naito T,Yanq H,et al. Sulodexide ameliorates early but not late kidneydisease in models of radiation nephropathy and diabetic nephropathy [J].Nephrol DialTransplant,2010,25(6):1803-1810.
3. Harenberg J.Review of pharmacodynamics,pharmacokinetics,and therapeuticproperties of sulodexide[J].Med Res Rev,1998,18(1):1-20.
4. Solini A,Carraro A,Barzon I,et a1.Therapy with glycosaminoglycans lowers albuminexcretion in non—insulin dependent diabetic patients withmicroalbuminuria[J],Diabetes Nutr Metab,1994,7:304-307.
5. Mogensen CE.Renal function changes in diabetes[J]. Diabetes,1976,25(Suppl):872-879.
6. de Zeeuw D,Remuzzi G,Parving HH,et al.Albuminuria,a therapeutic target forcardiovascular protection in type2diabetic patients withnephropathy[J].2004,110(8):921-927.
7. Broekhuizen LN,Lemkes BA,Mooij HL,et al.Effect of sulodexide on endothelialglycocalyx and vascular permeability in patients with type2diabetesmellitus[J].Diabetologia,2010,53(12):2646–2655.
8. Xu X,Rao G,Maxhimer JB.Mechanism of action of sulodexide-mediated control ofdiabetic proteinuria: inhibition of heparanase-1activity[J].Am SocNephrol,2005,16(4):673A.
9. Mcnica C,Giovanni G,Ulrich S,et al.Glycosaminoglycan therapy prevents TGF-β1overexpression and pathologic changes in renal tissue of long-term diabetic rats[J].AmSoc Nephrol,2000,11:2324–2336.
10. Shan CHEN,Zhan FANG,Zhonghua ZHU,et al.Protective Effect of Sulodexide onPodocyte Injury in Adriamycin nephropathy Rats[J].Huazhong Univ SciTechnol,2009,29(6):715-719．
11.舒冏，曾龙驿，王曼曼，等．舒洛地特对大鼠糖尿病肾脏的保护作用及其机制[J]．中国医院药学杂志，2009，29(1)：19-23．
12. Ciszewicz M,Polubinska A,Antoniewicz A,et al.Sulodexide suppresses inflammation inhuman endothelial cells and prevents glucose cytotoxicity[J].TranslRes,2009,153(3):118–123.
13. Gambaro G,Kinalska I,Oksa A,et al.Oral sulodexide reduces albuminuria inmicroalbuminuric and macroalbuminuric type1and type2diabetic patients:theDi.N.A.S.randomized trial. J Am Soc Nepphrol,2002,13(6):1615-1625.
14.张自沛．药理学实验．第二版．北京：人民卫生出版社，1996：238．
1. Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria inmicroalbuminuric and macroalbuminuric type1and type2diabetic patients: the Di.N.A.S. randomized trial[J]. J Am Soc Nephrol,2002,13(6):1615-1625.
2. Heerspink HL, Greene T, Lewis JB, et al. Effects of sulodexide in patients with type2diabetes and persistent albuminuria[J]. Nephrol Dial Transplant,2008,23(6):1946-1954.
3. Blouza S, Dakhli S, Abid H, et al. Efficacy of low-dose oral sulodexide in themanagement of diabetic nephropathy[J]. J Nephrol,2010,23(4):415-424.
4. Gu K, Zhao JD, Ren ZG, et al. A natural process of cirrhosis resolution anddeceleration of liver regeneration after thioacetamide withdrawal in a rat model[J]. MolBiol Rep,2011,38(3):1687-1696.
5. de Zeeuw D,Remuzzi G,Parving HH,et al.Albuminuria,a therapeutic target forcardiovascular protection in type2diabetic patients with nephropathy[J].2004,110(8):921-927.
6. Cooper ME, Vranes D, Yonssef S, et a1. Increased renal expression of vascularendothelial growth factor and its receptor VEGFR-2in experimental diabetes[J].Diabetes,1999,8(11):2229-2239.
7. Liu E, Morimoto M, Kitajima S, et a1. Increased Expression of Vascular EndothelialGrowth Factor in Kidney Leads to Progressive Impairment of Glomerular Functions[J].J Am Soc Nephrol,2007,18(7):2094–2104.
8. Veron D, Reidy KJ, Bertuccio C, et al. Overexpression of VEGF-A in podocytes ofadult mice causes glomerular disease[J]. Kidney International,2010,77(11):989–999.
9. Chen S, Ziyadeh FN. Vascular Endothelial Growth Factor and Diabetic Nephropathy[J].Current Diabetes Reports,2008,8(6):470–476.
10. Bates DO. Vascular endothelial growth factors and vascular permeability[J].Cardiovascular Research,2010,87(2):262–271.
11. Zeng L, Xu H, Chew TL, et al. HMG CoA reductase inhibition modulatesVEGF-induced endothelial cell hyperpermeability by preventing RhoA activation andmyosin regulatory light chain phosphorylation[J]. FASEB J,2005,19(13):1845–1847.
12. Chen S, Kasama Y, Lee JS, et al. Podocyte-derived vascular endothelial growth factormediates the stimulation of α3(IV)collagen production by transforming growthfactor-β1in mouse podocytes[J]. Diabetes,2004,53(1):2939–2949.
13. Sung SH, Ziyadeh FN, Wang A, et al. Blockade of vascular endothelial growth factorsignaling ameliorates diabetic albuminuria in mice[J]. J Am Soc Nephrol,2006,17(11):3093–3104.
14.孙昭，胡宗兰，丁晓红，等．低分子肝素对肿瘤细胞分泌血管内皮生长因子的影响[J]．中华肿瘤杂志，2009；31（11）：826-830．
15.甘良英，于仲元，蔡美顺，等．低分子质量肝素对糖尿病肾病大鼠肾血管内皮生长因子表达的影响[J]．北京大学学报（医学版），2005；37（4）：382-385．
16.顾红卫，倪兆慧，顾乐怡，等．血管生成素在糖尿病大鼠肾组织中的表达及氯沙坦的作用[J]．中国血液净化，2010；9（1）：32-36．
17. Kitamura S, Maeshima Y, Sugaya T, et al. Transforming growth factor-beta1inducesvascular endothelial growth factor expression in murine proximal tubular epithelialcells[J]. Nephron Exp Nephrol,2003,95(2):79-86.
18.林可意，曾龙驿，舒冏，等．舒洛地特对糖尿病大鼠尿白蛋白排泄率及肾脏转化生长因子-β1表达的影响[J]．中华糖尿病杂志，2009，1（3）：196-200．
19.张自沛．药理学实验(M)．第二版．北京：人民卫生出版社，1996：238．
1. Marrero MB, Banes-Berceli AK, Sten DM, et al. Role of the JAK/STAT signalingpathway in diabetic nephropathy. Am J Physiol Renal Physilol,2006,290(4):F762-F768.
2. Brosius FC, Ⅲ: New insights into the mechanisms of fibrosis and sclerosis in diabeticnephropathy. Rev Endocr Metab Disord,9(4):245-254.
3. Wanq X, Shaw S, Amiri F, et al. Inhibition of the JAK/STAT signaling pathwayprevents the high glucose-induced increase in tgf-beta and fibronectin synthesis inmesangial cells. Diabetes,51(12):3505-3509.
4. Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria inmicroalbuminuric and macroalbuminuric type1and type2diabetic patients: the Di.N.A.S. randomized trial[J]. J Am Soc Nephrol,2002,13(6):1615-1625.
5. Heerspink HL, Greene T, Lewis JB, et al. Effects of sulodexide in patients with type2diabetes and persistent albuminuria[J]. Nephrol Dial Transplant,2008,23(6):1946-1954.
6. Blouza S, Dakhli S, Abid H, et al. Efficacy of low-dose oral sulodexide in themanagement of diabetic nephropathy[J]. J Nephrol,2010,23(4):415-424.
7. Gu K, Zhao JD, Ren ZG, et al. A natural process of cirrhosis resolution anddeceleration of liver regeneration after thioacetamide withdrawal in a rat model[J]. MolBiol Rep,2011,38(3):1687-1696.
8. Duronio V, Scheid MP, Ettinger S. Downstream signalling events regulated byphosphatidylinositol3-kinase activity. Cell Signal,1998,10(4):233-239.
9. Kubo M, Hanada T, Yoshimura A. Suppressors of cytokine signaling and immunity.
10. Ortiz MG, Lopez PV, Lopez FO, et al. Suppressors of cytokine signaling abrogatediabetic nephropathy. J Am Soc Nephrol,2010,21(5):763-772.
11. Shi Y, Zhanq Y, Wanq C, et al. Suppressor of cytokine signaling-1reduces highglucose-induced TGF-beta1and fibronectin synthesis in human mesangial cells. FEBSLett,2008,582(23-24):3484-3488.
12. Shi Y, Du C, Zhanq Y, et al. Suppressor of cytokine signaling-1ameliorates expressionof MCP-1in diabetic nephropathy.2010,31(5):380-388.
1. Harenberg J,Review of pharmacodynamics,pharmacokinetics,and therapeutic propertiesof sulodexide[J].Med Res Rev,1998,18(1):1-20.
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○1上海交通大学附属第六人民医院肾内科（上海200233）