糖尿病肾病实验方法学及药物对糖尿病动物肾病的改善作用研究
|
摘要
糖尿病肾脏并发症严重威胁糖尿病患者的生活质量。无论是1型还是2型糖尿病患者，即使进行常规控制血糖的治疗，仍然有40％的患者最终出现肾脏并发症。在发达国家，因糖尿病肾病需要透析或肾移植治疗的终末期肾病大约占所有患者的40％。因而研究和开发治疗糖尿病肾病的药物具有重要意义。临床前实验研究是新药发现和研究的重要一环，本研究建立了有关糖尿病肾病临床前研究的几个重要方法，考察了1型和2型糖尿病动物模型的肾脏并发症发生和发展过程。并在1型和2型糖尿病动物模型上考察了几个化合物改善糖尿病肾脏并发症的作用及其作用机制。
临床前动物实验研究糖尿病肾病和一些其它类型的肾病时，最重要的检测指标是尿液微量白蛋白排泄量。冈为它直接反应了肾脏滤过功能的损害程度。本研究澄清了国内一些科研工作者在大小鼠尿液收集和尿液微量白蛋白测定上的若干模糊认识。建立了竞争性ELISA测定大鼠和小鼠尿液白蛋白的方法，该方法特异性强、易于推广，没有放射性污染，可定量测定大鼠和小鼠尿液微量白蛋白。用这种测定方法检测了1型、2型糖尿病大鼠模型以及2型糖尿病小鼠模型KKA~y小鼠的尿液白蛋白排泄量，相对于正常大鼠，糖尿病模型大鼠和小鼠均有尿液白蛋白排泄量的明显升高，提示这些动物有糖尿病肾脏并发症的出现。
非酶糖化终末产物是近些年来在包括肾病并发症在内的糖尿病慢性并发症研究中的一个热点，被认为在糖尿病以及糖尿病并发症的发生发展中是一个极重要的致病因素。本研究围绕非酶糖化终末产物做了三个方面的工作。一是结合国内外利用竞争性ELISA方法测定血清非酶糖化终末产物的文献资料，在本实验室制备了非酶糖化终末产物，用制备的非酶糖化终末产物免疫兔获得多克隆抗非酶糖化终末产物抗血清，进而建立了ELISA测定血清非酶糖化终末产物的方法，考察了吐温-20在测定中的作用。用这种方法测定1型糖尿病大鼠模型血清非酶糖化终末产物浓度，结果显示1型糖尿病模型大鼠血清非酶糖化终末产物明显升
About 40% diabetic patients develop kidney complications eventually. Diabetic nephropathy is a leading cause of end-stage renal failure, accounting for 35% to 40% of all new cases requiring dialysis therapy throughout the world. Preclinical study is very important for finding new drugs to treat, diabetic nephropathy. In this study several methods very useful to preclinical study of diabetic nephropathy were developed and the ameliorative effects of several agents on diabetic nephropathy in rat and mouse diabetic models were observed.
Part I A competitive ELISA for albumin in rat urine (attached: a competitive ELISA for albumin in mouse urine)
Nephropathy is characterized by urinary micro-albumin. Rat is usually used in experimental studies. But there was no specific and simple method for detecting rat urinary albumin. A specific, easily operated and sensitive method for quantitatively determining rat urinary albumin is needed. Using rabbit anti-rat albumin polyclonal antibody, a competitive ELISA for rat albumin in urine was developed. With this method the urinary albumin in diabetic and normal rats was detected. The rabbit anti-rat albumin polyclonal antibody showed no cross reaction with bovine, human serum albumin and rat IgG. Based on the cross-reaction of the rabbit anti-rat albumin antibody with mouse albumin, a competitive ELISA for mouse urinary albumin was also established. The urinary albumin markedly increased in diabetic rats and mice.
Part II Development and application of the ELISA method for measuring
临床前动物实验研究糖尿病肾病和一些其它类型的肾病时，最重要的检测指标是尿液微量白蛋白排泄量。冈为它直接反应了肾脏滤过功能的损害程度。本研究澄清了国内一些科研工作者在大小鼠尿液收集和尿液微量白蛋白测定上的若干模糊认识。建立了竞争性ELISA测定大鼠和小鼠尿液白蛋白的方法，该方法特异性强、易于推广，没有放射性污染，可定量测定大鼠和小鼠尿液微量白蛋白。用这种测定方法检测了1型、2型糖尿病大鼠模型以及2型糖尿病小鼠模型KKA~y小鼠的尿液白蛋白排泄量，相对于正常大鼠，糖尿病模型大鼠和小鼠均有尿液白蛋白排泄量的明显升高，提示这些动物有糖尿病肾脏并发症的出现。
非酶糖化终末产物是近些年来在包括肾病并发症在内的糖尿病慢性并发症研究中的一个热点，被认为在糖尿病以及糖尿病并发症的发生发展中是一个极重要的致病因素。本研究围绕非酶糖化终末产物做了三个方面的工作。一是结合国内外利用竞争性ELISA方法测定血清非酶糖化终末产物的文献资料，在本实验室制备了非酶糖化终末产物，用制备的非酶糖化终末产物免疫兔获得多克隆抗非酶糖化终末产物抗血清，进而建立了ELISA测定血清非酶糖化终末产物的方法，考察了吐温-20在测定中的作用。用这种方法测定1型糖尿病大鼠模型血清非酶糖化终末产物浓度，结果显示1型糖尿病模型大鼠血清非酶糖化终末产物明显升
About 40% diabetic patients develop kidney complications eventually. Diabetic nephropathy is a leading cause of end-stage renal failure, accounting for 35% to 40% of all new cases requiring dialysis therapy throughout the world. Preclinical study is very important for finding new drugs to treat, diabetic nephropathy. In this study several methods very useful to preclinical study of diabetic nephropathy were developed and the ameliorative effects of several agents on diabetic nephropathy in rat and mouse diabetic models were observed.
Part I A competitive ELISA for albumin in rat urine (attached: a competitive ELISA for albumin in mouse urine)
Nephropathy is characterized by urinary micro-albumin. Rat is usually used in experimental studies. But there was no specific and simple method for detecting rat urinary albumin. A specific, easily operated and sensitive method for quantitatively determining rat urinary albumin is needed. Using rabbit anti-rat albumin polyclonal antibody, a competitive ELISA for rat albumin in urine was developed. With this method the urinary albumin in diabetic and normal rats was detected. The rabbit anti-rat albumin polyclonal antibody showed no cross reaction with bovine, human serum albumin and rat IgG. Based on the cross-reaction of the rabbit anti-rat albumin antibody with mouse albumin, a competitive ELISA for mouse urinary albumin was also established. The urinary albumin markedly increased in diabetic rats and mice.
Part II Development and application of the ELISA method for measuring
引文
1. Neuman, R.G. and Cohen, M.P. Improved competitive enzyme-linked immunoassay (ELISA) for albuminuria. Clin Chim Acta. 1989, 179:229-238
2. Townsend J.C. A competitive immunoenzymometric assay for albumin in urine. Clin Chem. 1986, 32:1372-1374
3. Wang, L.; Pan, C.Y.; Huang, Z.J, et. al. Establishment of a radioimmunoassay method for urinary albumin excretion and the effect of ACEI on the excretion in rats. Chin J Endocrinol Metab. 1999, 15:164-167
4. Yue Ling Qie. Kazo Kaizu, Kohei Uriu, et. al. Measurement of urinary albumin using newly developed enzyme immunoassay in the rat. Clin Exp Nephrol. 2000, 4:99-104
5. Huijberts, M.S.P, Wolffenbuttel, B.H.R, Crijns, F.R.L, et. al. Aminoguanidine reduces regional albumin clearance but not urinary albumin excretion in streptozocin-diabetic rats. Diabetologia. 1994, 37:10-14
6. Soulis, T.; Cooper, M.E.; Sastra, S, et. al. Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats. Diabetologia. 1997, 40:1141-1151
7. Tanya, M.O, Yunxia, Y, Sianna, P, et. al. Prevention of albuminuria by aminoguanidine or ramipril in streptozotocin-induced diabetic rats is associated with the normalization of glomerular protein kinase C. Diabetes. 2000, 49:87-93
8. Carel J. Van Oss; Mark K. Hawking and Paul M, Bronson. A comparison between immunochemical and physical chemical analyses of the molecular size of urinary proteins. Biochemical Medicine. 1973, 7:466-472
9. Soulis T, Cooper ME, Vranes D, et. al. Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment. Kidney international. 1996, 50:627-634
10. Soulis-Liparota T, Cooper M, Papazoglou D, et. al. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin induced diabetic rat. Diabetes. 1991, 40:1328-1334
11. Kelly DJ, Zhang Y, Hepper C, et. al. Protein Kinase C-β Inhibition Attenuates the Progression of Experi mental Diabetic Nephropathy in the Presence of Continued Hypertension. Diabetes.2003??52: 512-518
12. Gilbert RE, Cox A, Wu LL, et, al. Expression of Transforming Growth Factor-β1 and Type Ⅳ Collagen in the Renal Tubulointerstitium in Experimental Diabetes Effects of ACE Inhibition.Diabetes. 1998, 47: 414-4221. Dominic S.C.Raj, Devasmita Choudhury, Tomas C.Welboume, et. al. Advanced Glycatiou End Products: A Nephrologist's Perspective. American Journal of Kidney Diseases. 2000, 35(3): 365-380
2. Daisuke Suzuki, Toshio Miyata, Noboru Saotome, et. al. Immunohistochemieal Evidence for an Increased Oxidative Stress and Carbonyl Modification of Proteins in Diabetic Glomerular Lesions.J Am Soc Nephrol. 1999, 10: 822-832
3. Tomonori Uchimura, Kazushi Nakano, Teruto Hashiguchi, et. al. Elevation of N-(Carboxy-methyl)valine Residue in Hemoglobin of Diabetic Patients Its role in the development of diabetic nephropathy. Diabetes Care. 2001, 24: 891-896
4. Tomoko Mitsuhashi, Yong Ming Li, Steven Fishbane, et. al. Depletion of Reactive Advanced Glycation Endproducts from Diabetic Uremic Sera Using a Lysozyme-linked Matrix. J.Clin.Invest. 2003, 100: 847-854
5. Andreas Tauer., Xiaohong Zhang, Thomas P.Schaub, et. al. Formation of Advanced Glycation End Products During CAPD. American Journal of Kidney Diseases. 2003, 41(3, Suppl 1): S57-S60
6. Chun-Liang Lin, Chiu-Ching Huang, Chun-Chen Yu, et. al. Reduction of Advanced Glycation End Product Levels by On-Line Hemodia-filtration in Long-Term Hemodialysis 0patients. Am J Kidney Dis. 2003, 42: 524-531
7. Wulf Palinski, Theodor Koschinsky, Susan W.Butler, et. al. Immunological Evidence for the Presence of Advanced Glycosylation End Pro-ducts in Atherosclerotic Lesions of Euglycemic Rabbits. Arteriosclerosis, Thrombosis, and Vascutlar Biology. 1995, 15: 571-582
8. Paul A.Voziyan, Thomas O.Metz, John W.Baynes, et. al. A Post-Amadori Inhibitor Pyridoxa-mine Also Inhibits Chemical Modification of Proteins by Scavenging Carbonyl Intermediates of Carbohydrate and Lipid Degradation. J Biol Chem. 2002, 277(5): 3397-34039. Ve Ronique Witko-Sarsat, Vale Rie Gausson, Anh-Thu Nguyen, et. al. AOPP-induced activation of human neutrophil and monocyte oxidative metabolism: A potential target for N-acetylcysteine treatment in dialysis patients. Kidney International. 2003, 64: 82-91
10. Joelle M.Onorato, Alicia J.Jenkins, Suzanne R.Thorpe, et. al. Pyridoxamine, an Inhibitor of Advanced Glycation Reactions, Also Inhibits Advanced Lipoxidation Reactions Mechanism of Action of Pyridoxamine. J Biol Chem. 2000, 275(28): 21177-21184
11. Miriam A.Friedlander, Yu Ching Wu, Abdelhamid Elgawish, et. al. Early and Advanced Glycosylation End Products Kinetics of Formation and Clearance in Peritoneal Dialysis.J.Clin.invest. 1996, 97: 728-735
12. Melissa M.Anderson, Jesus R.Requena, Jan R.Crowley, et.al. The myeloperoxidase system of human phagocytes generates Nε-(carboxy methyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation. J.Clin.invest. 1999, 104: 103-113
13. Daniel Cervantes-Laurean, Elaine L.Jacobson and Myron K.Jacobson. Glycation and Glycoxidation of Histories by ADP-ribose. J Biol Chem. 1996, 271(18): 10461-10469
14. Frederic Tessier, Mark Obrenovich and Vincent M.Monnier. Structure and Mechanism of Formation of Human Lens Fluorophore LM-1 Relationship to vesperlysine A and the Advanced Maillard Reaction in Aging, Diabetes, and Catatactogenesis. J Biol Chem. 1999, 274(30): 20796-20804
15. Ryoji Nagaiii, Cristina Mild Hayashiii, Ling Xia, et. al. Identification in Human Athero-sclerotic Lesions of GA-pyridine, a Novel Structure Derived from Glycolaldehyde-modified Proteins. J.Biol.Chem. 2002, 277(50): 48905-48912
16. Klaus M.Biemel, D.Alexander Friedl and Markus O.Lederer Identification and Quanti-fication of Major Maillard-Crosslinks in Human Serum Albumin and Lens Protein: Evidence for Glucosepane as the Dominant Compound. J Biol Chem. 2002, 277(28): 24907-24915
17. Noriko Uesugi, Noriyuki Sakata, Ryoji Nagai, et. al. Glycoxidative modification of AA amyloid deposits in renal tissue, nephrol dial transplant. 2000, 15: 355-365
18. Xingyu Wang, Richard Bucala, and Ross Miine.Epitopes close to the apolipoprotein B low density lipoprotein receptor-binding site are modified by advanced glyeation end products. Proc.Natl.Acad.Sci. 1998, 95: 7643-7647
19. Ramanakoppa H.Nagaraj, Irina N.Shipanova and Frederick M.Faust Protein Cross-linking by??the Maillard Reaction isolation, characterization, and in vivo detection of a lysine-lysine cross-link derived from methylglyoxal. J Biol Chem. 1996, 271(32): 19338-19345
20. Tomoko Oya, Nobutaka Hattori, Yoshikuni Mizuno, et. al. Methylglyoxal Modification of Protein, Chemical and Immunochernical Charac-terization of Methylglyoxal Arginine Adducts. J Biol Chem. 1999, 274(26): 18492-18502..
21. Marcus A.Glomb and Christoph Pfahler. Amides Are Novel Protein Modifications Formed by Physiological Sugars. J Biol Chem. 2003, 276(45): 41647, 41638-41647
22. Klaus M.Biemel, Oliver Reihl, Jurgen Conrad, et. al. Formation Pathways for Lysine-Arginine Crosslinks Derived from Hexoses and Pentoses by Maillard Processes: Unraveling the Structure of a Pentosidine Precursor Protein Cross-Linking by Maillard Processes. J Biol Chem. 2001,
23. Ryoji Nagail, Yuka Uuno, Mild Cristina Hayashil, et. al. Peroxynitrite Induces Formation of N-(Carboxymethyl)Lysine by the Cleavage of Amadori Product and Generation of Glucosone and Glyoxal From Glucose Novel Pathways for Protein Modification by Peroxynitrite. Diabetes 2002, 51: 2833-2839
24. Nobuko Miyazawa, Yoshimi Kawasaki, Junichi Fujii, et. al. Immunological detection of fructated proteins in vitro and in vivo. Biochem.J. 1998, 336: 101-107
25. Behnom Farboud, Amy Aotaki-Keen, Toshio Miyata, et. al. Development of a Polyclonal Antibody with Broad Epitope Specificity for Advanced Glycation Endproduets and Localization of these Epitopes in Bruch's Membrane of the Aging Eye. Molecular Vision. 1999, 5: 11-16
26. Xia Ling, Ryoji Nagai, Naomi Sakashita, et. al. Immunohistochemical Distribution and Quantitative Biochemical Detection of Advanced Glycatiun End Products in Fetal to Adult Rats and in Rats with Streptozotoein-Induced Diabetes. Laboratory Investigation 2001, 81: 845-861
27. Toshimitsu Niwa, Tomoyuki Katsuzaki, Shigeru Miyazakiii, et. al. Immunohistochemical Detection of Imidazolone, a Novel Advanced Glycation End Product, in Kidneys and Aortas of Diabetic Patients. J.Clin.invest. 1997, 99(6): 1272-1280
28. A.Ashley Booth, Raja G.Khalifah, Parvin Todd, et. al. In Vitro Kinetic Studies of Formation of Antigenic Advanced Glycation End Products (AGEs) Novel Inhibition of Post-amadori Glycation Pathways. J Biol Chem. 1997, 272(9): 5430-5437
29. David L.Price, Patricia M.Rhett, Suzanne R.Thorpe, et. al. Chelating Activity of Advanced Glycation End-product Irthibitors. J Biol Chem. 2001, 276(52): 48967-489721. Jeffrey I. K.reisberg, Morris J. Kamovsky. Glomerular cells in culture. Kidney International. 1983, 23: 439-447
2. R.M.Henderson, R.D.Barber. Ion channels in renal glomerular mesanggial cells. J. Membrane Biol. 1998, 163: 1-8
3. Mene P, Pugliese G, Pricci F, et. al. High Glucose inhibits cytosolic calcium signaling in cultured rat mesangial cells. Kidney International. 1993, 43: 585-591
4. D.Kunz, G.Walker and J.Pfeilschifter. Transforming growth factor-2 inhibits interleukin 1β-induced expression of inducible nitric oxide synthase in rat renal mesangial cells.??Inflammation Research 1997, 46:327-331
5. Toshifumi Tetsuka, Dorit Daphna-Iken, Brent W. Miller, et. al. Nitric oxide amplifies interleukin 1-induced cyclooxygenase-2 expression in rat mesangial cells. J. Clin. Invest. 1996, 97:2051-2056
6. R.Cermak, R.Kleta, W.G.Forssmann, et. al. Natriuretic peptides increase a K~+ conductance in rat mesangial cells. Eur J Physiol. 1996, 431:571-577
7. G. Wolf, R. Reinking, G. Zahner, et. al. Erk 1, 2 phosphorylates p27~(kip1):functional evidence for a role in high glucose induced hypertrophy of mesangial cells. Diabetologia. 2003, 46:1090-1099
8. Vincenzo Scivittard, Michael B. Ganz, and Miriam F. WeissAGEs induce oxidative stress and active protein kinase C- in neonatal mesangial cells. Am J Physiol Renal Physiol. 2000, 278:F676-F683
9. Margo P. Cohen, Fuad N. Ziyaden, Gregory T. Lautenslager, et. al. Glycated albumin stimulation of PKC-β activity is linked to increased collagen IV in mesangial cells. Am. J. Physiol. 1999, 276(Renal Physiol.45):F684-F690
10. Bing-Fen Liu, Satoshi Miyata, Yushi Hirota, et. al. Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells. Kidney International. 2003, 63:947-957
11. Winnie Chan, Kwei Chi Lin, Peck-Sun Lin, et. al. Growth inhibition of rat mesangial cells by high glucose: effect of vitamin E. Clin Exp Nephrol. 1999, 3:268-2711. G.Dogra, G.F.Watts.Genes and diabetic nephropathy: what have we learnt so far? Pract Diab Int.2000, 17(3): 84-90
2. Shinichi Nishi, Mitsuhiro Ueno, Shimada HisakiNoriaki Iino, et. al.Ultrastructural characteristics of diabetic nephropathy. Med Electron Microsc. 2000, 33: 65-73
3. Effie C Tsilibary. Microvascular basement membranes in diabetes mellitus. Journal of Pathology. 2003, 200: 537-546
4. Amanda I.Adler, Richard J.Stevens, Sue E.Manley, et. al.Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney International. 2003, 63: 225-232
5. Ryuichi Kikkawa, Daisuke Koya, and Masakazu Haneda.Progression of diabetic nephropathy. American Journal of Kidney Diseases. 2003, 41(3, Suppl 1): S19-S21
6. Christoph Hasslacher. "Diabetic Nephropathy",. 2001.
7. Giuseppe D'Amico and Claudio Bazzi.Pathophysiology of proteinuria. Kidney International 2003, 63(3): 809-825
8. M.Luiza Caramori, Paola Fioretto, and Michael Mauer. Perspectives in diabetes the need for early predictors of diabetic nephropathy risk is albumin excretion rate sufficient? Diabetes. 2000, 49: 1399-1408
9. Tanya M.Osicka, Yunxia Yu, Sianna Panagiotopoulos.Prevention of albuminuria by??aminoguanidine or ramipril in streptozotocin induced diabetic rats I s associated with the normalization of glomerular protein kinase C. Diabetes. 2000, 49:87-93
10. Eli A.Friedman. Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications. Diabetes Care. 1999, 22(Suppl. 2):B65-B71
11. Michael Brownlee. Advanced protein glycosylation in diabetes and aging. Annu.Rev.Med. 1995, 46:223-234
12. Dominic S.C.Raj, Devasmita Choudhury, Tomas C.Welbourne. Advanced glycation end products: a nephrologist's perspective. American Journal of Kidney Diseases. 2000, 35(3):365-380
13. Katsunori Horie, Toshio Miyata, Kenji Maeda, et. al. Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J.Clin.Invest. 1997, 100:2995-3004
14. E.A.Friedman. Advanced glycation end products in diabetic nephropathy. Nephrol dial transplant. 1999, 14(supple3):1-9
15. August Heidland, Katarina Sebekova, and Reinhard Schinzel. Advanced glycation end products and the progressive course of renal disease. American Journal of Kidney Diseases. 2003, 38(4, Suppl 1):S100-S106
16. Zolta'n Wagner, Istva'n Wittmann, Istva'n Maza'k, et. al. Ne-(carboxymethyl) lysine levels in patients with type 2 diabetes: role of renal function. American Journal of Kidney Diseases. 2003, 38(4):785-791
17. Mark E.Williams. New therapies for advanced glycation end product nephrotoxicity: current challenges. American Journal of Kidney Diseases. 2003, 41(3, Suppl 1):S42-S47
18. Tomonori Uchimura, Kazushi Nakano, Teruto Hashiguchi, et. al. Elevation of N-(carboxymethyl)valine residue in hemoglobin of diabetic patients its role in the development of diabetic nephropathy. Diabetes Care. 2001, 24:891-896
19. Katary(?)na S ebekova, Veronika Faist, Thomas Hofmann, et. al.Effects of a diet rich in advanced glycation end products in the rat remnant kidney model. American Journal of Kidney Diseases. 2003, 41(3, Suppl 1): S48-S51
20. Feng Zheng, Cijiang He, Weijing Cai, et. al. Prevention of diabetic nephropathy in mice by a diet low in glycoxidation products. Diabetes/Metabolism Research and Reviews. 2002,??18:224-237
21. Cijiang He, Jennifer Sabol, Tomoko Mitsuhashi, et. al. Dietary glycotoxins inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration. Diabetes. 1999, 48: 1308-1315
22. I.london O and M.Bendayan. Temporary effects of circulating amadori products on glomerular filtration properties in the normal mouse. Am J Physiol Renal Physiol. 2001, 280:F103-F111
23 D.H.Atchley, M.F.Lopes-Virella 1, D.Zheng, et. al.Oxidized LDL-anti-oxidized LDL immune complexes and diabetic nephropathy. Diabetologia. 2002, 45(11): 1562-1571
24. Marina A.Mironova, Richard L.Klein, Gabriel T. Virella, et.al. Anti-modified LDL antibodies, LDL-containing immune complexes, and susceptibility of LDL to in vitro oxidation in patients with Type 2 diabetes. Diabetes. 2000, 49:1033-1041
25. Xing Yu Wang, Richard Bucala and Ross Miline. Epitopes close to the apolipoprotein B low density lipoprotein receptor-binding site are modified by advanced glycation end products. Proc.Natl.Acad.Sci. 1998, 95:7643-7647
26. Trevor J.Orchard, Gabriel Virella, Kimberly Y.Z.Forrest, et.al Antibodies to oxidized LDL predict coronary artery disease in Type 1 diabetes a nested case-control study from the Pittsburgh epidemiology of diabetes complications study. Diabetes. 1999, 48:1454-1458
27. Rie Shibayama, None Araki, Ryoji Nagai, et.al.Autoantibody against N-(carboxymethyl)lysine an advanced glycation end product of the maillard reaction. Diabetes. 1999, 48:1842-1849
28. Ve'ronique Witko-Sarsat, Miriam Friedlander, Thao Nguyen Khoa, et.al. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure 1. The Journal of Immunology. 1998, 61:2524-2532
29. Caroline Sassy-Prigent, Didier Heudes, Chantal Mandet, et.al. Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes. 2000, 49(3):466-475
30. Richard K.M. Wong, Andrew I. Pettit, Joan E. Davies, et. al. Augmentation of the neutrophil respiratory burst through the action of advanced glycation end products a potential contributor to vascu(?)lar oxidant stress. Diabetes. 2002, 51:2846-2853
31. Peter Reaven, Shiva Merat, Florencia Casanada, et.al. Effect of streptozotocin-induced hyperglycemia on lipid profiles, formation of advanced glycation endproducts in lesions, and??extent of atherosclerosis in LDL receptor-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997, 17:2250-2256
32. Thorsten P.Degenhardt, Nathan L.Alderson, David D.Arrington, et.al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney International. 2002, 61:939-950
33. Joelle M.Onorato, Alicia J.Jenkins, Suzanne R.Thorpe, et.al. Pyridoxamine, an inhibitor of advanced glycation reactions, also Inhibits advanced lipoxidation reactions mechanism of action of pyridoxamine. J Biol Chem. 2000, 275(28):21177-21184
34. Paul A.Voziyan, Thomas O.Metz, John W.Baynes, et. al. A post-amadori inhibitor pyridoxamine also inhibits chemical modification of proteins by scavenging carbonyl intermediates of carbohydrate and lipid degradation. J Biol Chem. 2002, 277(5):3397-3403
35. Ida Giardino, Annan K.Fard, Diane L.Hatchell, et.al. Aminoguanidine inhibits reactive oxygen species formation, lipid peroxidation, and oxidant-induced apoptosis. Diabetes. 1998, 47:1114-1120
36. D.Bonefont-Rousselot, J.P.Bastard, M.C.Jaudon, et.al. Consequences of the diabetic status on the oxidant/antioxidant balance. Diabetes & Metabolism. 2000, 26:163-176
37. Jakus V. The role of free radicals, oxidative stress and antioxidant systems in diabetic vascular disease. Bratisl Lek Listy. 2000, 101(10):541-551
38. Vincenzo Scivittaro, Michael B.Ganz, and Miriam F.Weiss. AGEs induce oxidative stress and activate protein kinase C-bII in neonatal mesangial cells. Am J Physiol Renal Physiol. 2000, 278:F676-F683
39. Daisuke Suzuki, Toshio Miyata, Noboru Saotome, et.al. Immunohistochemical evidence for an increased oxidative stress and carbonyl modification of proteins in diabetic glomerular lesions. J Am Soc Nephrol. 1999, 10:822-832
40. Howard Trachtman, Stephen Futterweit, Elyse PineJared Mann, et. al. Chronic diabetic nephropathy: role of inducible nitric oxide synthase. Pediatr Nephrol. 2002, 17:20-29
41. Roland Veelken, Karl F.Hilgers, Andrea Hartner, et.al. Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy. J Am Soc Nephrol. 2000, 11:71-79
42. T. Soulis 1, M.E. Cooper 1, S. Sastra 1, et. al. Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats.??Diabetologia. 1997, 40: 1141-1151
43. W.Brian Reeves and Thomas E.Andreoli T. Transforming growth factor b contributes to progressive diabetic nephropathy. PNAS. 2000, 97(14):7667-7669
44. Fuad N.Ziyadeh, Brenda B.Hoffman, Dong Cheol Han, et.al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal anti transforming growth factor-b antibody in db/db diabetic mice. PNAS. 2002, 97:8015-8020
45. Darren J.Kelly, Richard E.Gilbert, Alison J.Cox, et.al. Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy. J Am Soc Nephrol. 2001, 12:2098-2107
46. J.W.van der Pijl, M.R.Daha, J.van den Born, et.al. Extracellular matrix in human diabetic nephropathy: reduced expression of heparan sulphate in skin basement membrane. Diabetologia 1998, 41:791-798
47. Giovanni Gambaro and Fokko J.Van Der Woude. Glycosaminoglycans use in treatment of diabetic nephropathy. J Am Soc Nephrol. 2000, 11:359-368
48. Tore Julsrud Berg, Phdper Hilderbrandt. Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes. Diabetes Care. 1999, 22(7):1186-1190
49. Gavin R.Norton, Geoff Candy. Aminoguanidine prevents the decreased myocardial compliance produced by streptozotocin-induced diabetes mellitus in rats. Circulation 1996, 93:1905-1912
50. Mohammad Asif, John Egan, Sara Vasan, et.al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. PNAS. 2000, 97(6):2809-2813
51. Jonathan R. Rumble, Mark E. Cooper, Tina Soulis, et. al. Vascular hypertrophy in experimental diabetes role of advanced glycation end products. J. Clin. Invest. 1997, 99:1016-1027
52. Bruce H.R.Wolffenbuttel, Chantal M.Boulanger, Francy R.L.Crijns. Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc.Natl.Acad.Sci. 1998, 95:4630-4634
53. Bruno Corman, Micheline Duriez, Pierre Poitevin, et.al. Aminoguanidine prevents age-related arterial stiffening and cardiac hypertrophy. PNAS. 1998, 95(3): 1301-130654. Alan Stitt, Thomas A.Gardiner, Nathan L.Anderson, et.al. The AGE Inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes. 2002, 51:2826-2832
55. Mitsushi Inomata, Masami Hayashi, Seigo Shumiya. Aminoguanidine-treatment results in the inhibition of lens opacification and calpain-mediated proteolysis in Shumiya cataract rats (SCR). J.Biochem. 2000, 128: 771-776
56. Timothy S.Kern 1 and Ronald L.Engerman. Pharmacological inhibition of diabetic retinopathy aminoguanidine and aspirin. Diabetes 2001, 50:1636-1642
57. Jennifer L.Wilkinson-Berka, Darren J.Kelly, Suzanne M.Koerner, et.al. ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mREN-2)27 rat. Diabetes. 2002, 51:3283-3289
58. P.H.Yu, D.M.Zuo.Aminoguanidine inhibits semicarbazide-sensitive amine oxidase activity: implications for advanced glycation and diabetic complications. Diabetologia. 1997, 40:1243-1250
59. Leon A.Bach, Rachael Dean, Sherrif Youssef, et. al. Aminoguanidine ameliorates changes in the IGF system in experimental diabetic nephropathy. nephrol dial transplant. 2000, 15:347-354
60. H.Sugimoto 1, K. Shikata 1, J. Wada 1, et. al. Advanced glycation end products- cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-a and inducible nitric oxide synthase in diabetic rat glomeruli. Diabetologia. 1999, 42: 878-886
61. A.Ashley Booth, Raja G. Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glucation end products: comparision of aminoguanidine. Biochemical and biophysical research communications. 1996, 220:113-119
62. Daisuke Koya and George L.King. Perspectives in diabetes protein kinase C activation and the development of diabetic complications. Diabetes. 1998, 47:859-866
63. Katherine R.Tuttle, and Pamela W.Anderson. A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C inhibition. American Journal of Kidney Diseases. 2003, 42(3): 456-465
64. Daisuke Koya, Masakazu Haneda, Hiroko Nakagawa, et.al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC-βinhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. The FASEB Journal. 2000, 14:439-44765. Tina Soulis-Liparota, Mark Cooper, Dimitria Papazoglou. Retardation by amino- guanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes. 1991, 40:1328-13341. Hi Bahl Lee, Hunjoo Ha, Sung Il Kim, and Fuad N.Ziyadeh. Diabetic kidney disease research: Where do we stand at the turn of the century ? Kidney International. 2000, 58(Supp177): S1-S2
2. Dominic S.C.Raj, Devasmita Choudhury, Tomas C.Welboume. et. al. Advanced Glycation End Products: A Nephrologist's Perspective. American Journal of Kidney Disease. 2000, 135: 365-380
3. A.Gugliuccl and T.Menini. Circulating Advanced Glycation Peptides in Streptozotocin induced Diabetic Rats: Evidence for Preferential Modification of IgG Light Chains. Life Science. 1998, 62: 2141-2150
4. R.Singh, A.Barden, T.Mori, L.Beilin. Advanced glycation end products: a review. Diabetologia.2001, 44: 129-146
5. Sherif Youssfe, Dominique T.Nguyen, Tina Soulis, et. al. Effect of diabetes and aminoguanidine therapy on renal advanced glycation end-product binding. Kidney International.1999, 55: 907-916
6. Giuseppe Pugliese, Flavia Pricci, Gaetano Leto, et. al. The Diabetic Milieu Modulates the Advanced Glycation End Product-Receptor Complex in the Mesangium by Inducing or Upregulating Galectin-3 expression. Diabetes. 2000, 49: 1249-1257
7. Nobushige Tanaka, hideto Yonekura, Sho-ichi Yamagishi, et. al. The Receptor for Advanced??Glycation End Products Is Induced by the Glycation Prooducts Themselves and Tumor Necrosis Factor-a through Nuclear Factor-kB, and by 17b-Estrdiol through Sp-1 in Human Vascular Endothelial Cells; The Journal of Biological Chemistry. 2000, 275: 25781-25790
8. Tina Soulis, Mark E.Cooper, Dimitria Vranes, Richard Bucala, et. al. Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment. Kidney International. 1996, 50:627-634
9. Tomoko Shimoike, toyoshi Inoguchi, Fumio Umeda, et. al. The Meaning of Serum Levels of Advanced Glycation End Products in Diabetic Nephropathy. Metabolism. 2000, 49:1030-1035
10. Mark E.Cooper, Richard E.Gilbert, and Murray Epstein. Pathophysiology of Diabetic Nephropathy. Metabolism. 1998, 47(Suppl l):3-6
11. Michael Browniee. Negative Consequences of glycation. Metabolism. 2000, 49(Suppl 1):9-13
12. Verbeke P, Perichon M, Friguet B, Bakala H, et. al. Inhibition of nitric oxide synthase activity by early and advanced glycation end products in cultured rabbit proximal tubular epithelial cells. Biochim Biophys Acta. 2000, 1502(3):481-494
13. Heidland A, Sebekova K, Schinzel R, et. al. Advanced glycation end products and the progressive course of renal disease. Am J Kidney Dis. 2001, 38(4 Suppl 1):S100-106
14. Guangsheng Xiang, Reinhard Schinzei, Andreas Simm, Katarina Sebekova, et. al. Advanced glycation end products impair protein turnover in LLC-PK1: Ame- lioration by trypsin. Kidney International. 2001, 59(Suppl.78): S-53-S-57
15. Iwashima Y, Eto M, Horiuchi S, Sano H, et. al. Advanced glycation end product-induced peroxisome proliferator-activated re- ceptor gamma gene expression in the cultured mesangial cells. Biochem Biophys Res Commun. 1999, 264(2):441-8
16. Mene P, Pascale C, Teti A, Bernardini S, et. al. Effects of advanced glycation end products on cytosolic Ca2 signaling of cultured human mesangial cells. J Am Soc Nephrol. 1999, 10:1478-1486
17. Deng Y, Chen X, Ye Y. Effects of glycated protein on the expression of plasminogen activator inhibitor-1 of cultured human mesangial cells. NATIONAL MEDICAL JOURNAL OF CHINA 1997, 77(9):672-675
18. Pugliese G, Pricci F, Romeo G, et. al. Upregulation of mesangial growth factor and extracellular matrix synthesis by advanced glycation end products via a receptor-mediated??mechanism. Diabetes. 1997, 46: 1881-1887
19. Iehara N, Takeoka H, Yamada Y, et. al. Advanced glycation end products modulate transcriptional regulation in mesangial cells. Kidney Int. 1996, 50: 1166-1172
20. Throckmorton DC, Brogden AP, Min B, Rasmussen H, et. al. PDGF and TGF-beta mediate collagen production by mesangial cells exposed to advanced glycosylation end products. Kidney Int. 1995, 48: 111-117
21. Kim YS, Kim BC, Song CY, et. al. Advanced glycosylation end products stimulate collagen mRNA synthesis in me-sangial ceils mediated by protein kinase C and transforming growth factor-beta. J Lab Clin Med. 2001, 138: 59-68
22. Patrizo R Oddetti, Antonella Borgoglio, Angelo De Pascale, et. al. Prevention of Diabetes-increased Aging Effect on Rat Collagen-linked Fluores-cence by Aminoguanidine and Rutin. Diabetes. 1990, 39: 796-801
23. Winnie Deuther-Conrad, Sybille Franke, Manfred Sommer, et. al. Difference in the modulating potential of advanced glycation end product (age) peptides versus AGE proteins. Kidney International. 2001, 59(Supp178): S-63-S-66
24. Suree Jianmongkol, Jennifer L. Vuletich, Andrew T. Bender, et. al. Aminoguanidine mediated Inactivation and Alteration of Neuronal Nitric-oxide Synthase. The Journal of Biological Chemistry. 2000, 275: 13370-13376
25. T.Soulis, M.E.Cooper, S.Satra, et. al. Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediaed renoprotection in diabetic rats. Diabetologia.1997, 40: 1141-1151.
26. B.O.Nilsson. Biological efects of aminoguanidine: An update. Inflammation Research. 1999, 48: 509-515
27. M.S.P.huijberts, B.H.R.Wolffenbuttel, F.R.L.Crijns, et. al. Aminoguanidine reduces regional albumin clearance but not urinary albumin excretion in streptozotocin-diabetic rats. Diabetologia. 1994, 37: 10-14.
28. TanyaM.Osicka, YunxiaYu, Sianna Panagiotopoulos, et. al. Prevention of Albuminuria by Aminoguanidine or Ramiprilin Streptozotocin-induced Diabetic Rats Is Associated With the Normalization of Glomerular Protein Kinase C. Diabetes. 2000, 49: 87-93
29. Tina Soulis-liparota, Mark Cooper, Dimitria Papazoglou, et. al. Retardation by??Aminoguanidine of Development of Albuminuria, Mesangial Expansion, and Tissue Fluorescence in Streptozocin-induced Diabetic Rat. Diabetes. 1991, 40:1328-1334
30. Leon A.Bach, Rachael Dean, Shrrif Youssef, et. al. Aminoguanidine ameliorates changes in the IGF system in experimental diabetic nephropathy. Nephrol Dial Transplant. 2000, 15:347-354
31. Sung-Hee Ihm, Hyung Joon Yoo, Sung Woo Park, et. al. Effect of Aminoguanidine on Lipid Peroxidation in Streptozotocin-Induced Diabetic Rats. Metabolism. 1999, 48:1141-1145
32. Shinsuke Hiramatsu, Kauru Inoue, Yuji Tajirl, et. al. Impovement by Aminoguanidine of Insulin Secretion from Pancreatic Islets Grafted to Syngeneic Diabetic Rats. Biochemical Pharmacology. 2000, 60:263-268
33. Paulina Sannomiya, Maria Aoliveira & Zuleica B. Fortes. Aminoguanidine and the prevention of leukocyte dysfunction in diabetes mellitus: a direct vital microscopic study. British Journal of Pharmacology. 1997, 122:894-898
34. J.M.Forbes, T.Soulis, V.Thallas, et. al. Renoprotective effects of a novel inhibitor of advanced glycation. Diabetologia. 2001, 44:108-114
35. Peter S. Oturai, Mogens Christensen, Bidda Rolin, et. al. Effects of Advanced Glycation End-Product Inhibition and Cross-Link Breakage in Diabetic Rats. Metabolism. 2000, 49(8):996-1000
36. Seikoh Horiuchi, None Araki, and Yoshimasa Morino. Immunochemical Approach to Characterize Advanced Glycation End Products of the Maillard Reaction. The Jounal of Biological Chemistry. 1991, 266:7329-7332
37. Rie Shibayama, None Araki, Ryoji nagai, et. al. Autoantibody against N~ε-(carboxymethyl)lysine an advanced glycation end pro- duct of the maillard reaction. Diabetes. 1999, 48: 1842-1849
38. Katarina Sebekova, Pavol Blazicer, Dagmar Syrova, et. al. Circulating advanced glycation end product levels in rats rapidly increase with acute renal failure. Kidney International. 2001, 59(Suppl.78):S-58-S-62
39. Toshio Miyata, Satoshi Sugiyama, Akira Saito, et. al. Reactive carbonyl compounds related uremic toxicity ("carbonyl stress"). Kidney International. 2001, 59(Suppl.78):S-25-S-31
2. Townsend J.C. A competitive immunoenzymometric assay for albumin in urine. Clin Chem. 1986, 32:1372-1374
3. Wang, L.; Pan, C.Y.; Huang, Z.J, et. al. Establishment of a radioimmunoassay method for urinary albumin excretion and the effect of ACEI on the excretion in rats. Chin J Endocrinol Metab. 1999, 15:164-167
4. Yue Ling Qie. Kazo Kaizu, Kohei Uriu, et. al. Measurement of urinary albumin using newly developed enzyme immunoassay in the rat. Clin Exp Nephrol. 2000, 4:99-104
5. Huijberts, M.S.P, Wolffenbuttel, B.H.R, Crijns, F.R.L, et. al. Aminoguanidine reduces regional albumin clearance but not urinary albumin excretion in streptozocin-diabetic rats. Diabetologia. 1994, 37:10-14
6. Soulis, T.; Cooper, M.E.; Sastra, S, et. al. Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats. Diabetologia. 1997, 40:1141-1151
7. Tanya, M.O, Yunxia, Y, Sianna, P, et. al. Prevention of albuminuria by aminoguanidine or ramipril in streptozotocin-induced diabetic rats is associated with the normalization of glomerular protein kinase C. Diabetes. 2000, 49:87-93
8. Carel J. Van Oss; Mark K. Hawking and Paul M, Bronson. A comparison between immunochemical and physical chemical analyses of the molecular size of urinary proteins. Biochemical Medicine. 1973, 7:466-472
9. Soulis T, Cooper ME, Vranes D, et. al. Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment. Kidney international. 1996, 50:627-634
10. Soulis-Liparota T, Cooper M, Papazoglou D, et. al. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin induced diabetic rat. Diabetes. 1991, 40:1328-1334
11. Kelly DJ, Zhang Y, Hepper C, et. al. Protein Kinase C-β Inhibition Attenuates the Progression of Experi mental Diabetic Nephropathy in the Presence of Continued Hypertension. Diabetes.2003??52: 512-518
12. Gilbert RE, Cox A, Wu LL, et, al. Expression of Transforming Growth Factor-β1 and Type Ⅳ Collagen in the Renal Tubulointerstitium in Experimental Diabetes Effects of ACE Inhibition.Diabetes. 1998, 47: 414-4221. Dominic S.C.Raj, Devasmita Choudhury, Tomas C.Welboume, et. al. Advanced Glycatiou End Products: A Nephrologist's Perspective. American Journal of Kidney Diseases. 2000, 35(3): 365-380
2. Daisuke Suzuki, Toshio Miyata, Noboru Saotome, et. al. Immunohistochemieal Evidence for an Increased Oxidative Stress and Carbonyl Modification of Proteins in Diabetic Glomerular Lesions.J Am Soc Nephrol. 1999, 10: 822-832
3. Tomonori Uchimura, Kazushi Nakano, Teruto Hashiguchi, et. al. Elevation of N-(Carboxy-methyl)valine Residue in Hemoglobin of Diabetic Patients Its role in the development of diabetic nephropathy. Diabetes Care. 2001, 24: 891-896
4. Tomoko Mitsuhashi, Yong Ming Li, Steven Fishbane, et. al. Depletion of Reactive Advanced Glycation Endproducts from Diabetic Uremic Sera Using a Lysozyme-linked Matrix. J.Clin.Invest. 2003, 100: 847-854
5. Andreas Tauer., Xiaohong Zhang, Thomas P.Schaub, et. al. Formation of Advanced Glycation End Products During CAPD. American Journal of Kidney Diseases. 2003, 41(3, Suppl 1): S57-S60
6. Chun-Liang Lin, Chiu-Ching Huang, Chun-Chen Yu, et. al. Reduction of Advanced Glycation End Product Levels by On-Line Hemodia-filtration in Long-Term Hemodialysis 0patients. Am J Kidney Dis. 2003, 42: 524-531
7. Wulf Palinski, Theodor Koschinsky, Susan W.Butler, et. al. Immunological Evidence for the Presence of Advanced Glycosylation End Pro-ducts in Atherosclerotic Lesions of Euglycemic Rabbits. Arteriosclerosis, Thrombosis, and Vascutlar Biology. 1995, 15: 571-582
8. Paul A.Voziyan, Thomas O.Metz, John W.Baynes, et. al. A Post-Amadori Inhibitor Pyridoxa-mine Also Inhibits Chemical Modification of Proteins by Scavenging Carbonyl Intermediates of Carbohydrate and Lipid Degradation. J Biol Chem. 2002, 277(5): 3397-34039. Ve Ronique Witko-Sarsat, Vale Rie Gausson, Anh-Thu Nguyen, et. al. AOPP-induced activation of human neutrophil and monocyte oxidative metabolism: A potential target for N-acetylcysteine treatment in dialysis patients. Kidney International. 2003, 64: 82-91
10. Joelle M.Onorato, Alicia J.Jenkins, Suzanne R.Thorpe, et. al. Pyridoxamine, an Inhibitor of Advanced Glycation Reactions, Also Inhibits Advanced Lipoxidation Reactions Mechanism of Action of Pyridoxamine. J Biol Chem. 2000, 275(28): 21177-21184
11. Miriam A.Friedlander, Yu Ching Wu, Abdelhamid Elgawish, et. al. Early and Advanced Glycosylation End Products Kinetics of Formation and Clearance in Peritoneal Dialysis.J.Clin.invest. 1996, 97: 728-735
12. Melissa M.Anderson, Jesus R.Requena, Jan R.Crowley, et.al. The myeloperoxidase system of human phagocytes generates Nε-(carboxy methyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation. J.Clin.invest. 1999, 104: 103-113
13. Daniel Cervantes-Laurean, Elaine L.Jacobson and Myron K.Jacobson. Glycation and Glycoxidation of Histories by ADP-ribose. J Biol Chem. 1996, 271(18): 10461-10469
14. Frederic Tessier, Mark Obrenovich and Vincent M.Monnier. Structure and Mechanism of Formation of Human Lens Fluorophore LM-1 Relationship to vesperlysine A and the Advanced Maillard Reaction in Aging, Diabetes, and Catatactogenesis. J Biol Chem. 1999, 274(30): 20796-20804
15. Ryoji Nagaiii, Cristina Mild Hayashiii, Ling Xia, et. al. Identification in Human Athero-sclerotic Lesions of GA-pyridine, a Novel Structure Derived from Glycolaldehyde-modified Proteins. J.Biol.Chem. 2002, 277(50): 48905-48912
16. Klaus M.Biemel, D.Alexander Friedl and Markus O.Lederer Identification and Quanti-fication of Major Maillard-Crosslinks in Human Serum Albumin and Lens Protein: Evidence for Glucosepane as the Dominant Compound. J Biol Chem. 2002, 277(28): 24907-24915
17. Noriko Uesugi, Noriyuki Sakata, Ryoji Nagai, et. al. Glycoxidative modification of AA amyloid deposits in renal tissue, nephrol dial transplant. 2000, 15: 355-365
18. Xingyu Wang, Richard Bucala, and Ross Miine.Epitopes close to the apolipoprotein B low density lipoprotein receptor-binding site are modified by advanced glyeation end products. Proc.Natl.Acad.Sci. 1998, 95: 7643-7647
19. Ramanakoppa H.Nagaraj, Irina N.Shipanova and Frederick M.Faust Protein Cross-linking by??the Maillard Reaction isolation, characterization, and in vivo detection of a lysine-lysine cross-link derived from methylglyoxal. J Biol Chem. 1996, 271(32): 19338-19345
20. Tomoko Oya, Nobutaka Hattori, Yoshikuni Mizuno, et. al. Methylglyoxal Modification of Protein, Chemical and Immunochernical Charac-terization of Methylglyoxal Arginine Adducts. J Biol Chem. 1999, 274(26): 18492-18502..
21. Marcus A.Glomb and Christoph Pfahler. Amides Are Novel Protein Modifications Formed by Physiological Sugars. J Biol Chem. 2003, 276(45): 41647, 41638-41647
22. Klaus M.Biemel, Oliver Reihl, Jurgen Conrad, et. al. Formation Pathways for Lysine-Arginine Crosslinks Derived from Hexoses and Pentoses by Maillard Processes: Unraveling the Structure of a Pentosidine Precursor Protein Cross-Linking by Maillard Processes. J Biol Chem. 2001,
23. Ryoji Nagail, Yuka Uuno, Mild Cristina Hayashil, et. al. Peroxynitrite Induces Formation of N-(Carboxymethyl)Lysine by the Cleavage of Amadori Product and Generation of Glucosone and Glyoxal From Glucose Novel Pathways for Protein Modification by Peroxynitrite. Diabetes 2002, 51: 2833-2839
24. Nobuko Miyazawa, Yoshimi Kawasaki, Junichi Fujii, et. al. Immunological detection of fructated proteins in vitro and in vivo. Biochem.J. 1998, 336: 101-107
25. Behnom Farboud, Amy Aotaki-Keen, Toshio Miyata, et. al. Development of a Polyclonal Antibody with Broad Epitope Specificity for Advanced Glycation Endproduets and Localization of these Epitopes in Bruch's Membrane of the Aging Eye. Molecular Vision. 1999, 5: 11-16
26. Xia Ling, Ryoji Nagai, Naomi Sakashita, et. al. Immunohistochemical Distribution and Quantitative Biochemical Detection of Advanced Glycatiun End Products in Fetal to Adult Rats and in Rats with Streptozotoein-Induced Diabetes. Laboratory Investigation 2001, 81: 845-861
27. Toshimitsu Niwa, Tomoyuki Katsuzaki, Shigeru Miyazakiii, et. al. Immunohistochemical Detection of Imidazolone, a Novel Advanced Glycation End Product, in Kidneys and Aortas of Diabetic Patients. J.Clin.invest. 1997, 99(6): 1272-1280
28. A.Ashley Booth, Raja G.Khalifah, Parvin Todd, et. al. In Vitro Kinetic Studies of Formation of Antigenic Advanced Glycation End Products (AGEs) Novel Inhibition of Post-amadori Glycation Pathways. J Biol Chem. 1997, 272(9): 5430-5437
29. David L.Price, Patricia M.Rhett, Suzanne R.Thorpe, et. al. Chelating Activity of Advanced Glycation End-product Irthibitors. J Biol Chem. 2001, 276(52): 48967-489721. Jeffrey I. K.reisberg, Morris J. Kamovsky. Glomerular cells in culture. Kidney International. 1983, 23: 439-447
2. R.M.Henderson, R.D.Barber. Ion channels in renal glomerular mesanggial cells. J. Membrane Biol. 1998, 163: 1-8
3. Mene P, Pugliese G, Pricci F, et. al. High Glucose inhibits cytosolic calcium signaling in cultured rat mesangial cells. Kidney International. 1993, 43: 585-591
4. D.Kunz, G.Walker and J.Pfeilschifter. Transforming growth factor-2 inhibits interleukin 1β-induced expression of inducible nitric oxide synthase in rat renal mesangial cells.??Inflammation Research 1997, 46:327-331
5. Toshifumi Tetsuka, Dorit Daphna-Iken, Brent W. Miller, et. al. Nitric oxide amplifies interleukin 1-induced cyclooxygenase-2 expression in rat mesangial cells. J. Clin. Invest. 1996, 97:2051-2056
6. R.Cermak, R.Kleta, W.G.Forssmann, et. al. Natriuretic peptides increase a K~+ conductance in rat mesangial cells. Eur J Physiol. 1996, 431:571-577
7. G. Wolf, R. Reinking, G. Zahner, et. al. Erk 1, 2 phosphorylates p27~(kip1):functional evidence for a role in high glucose induced hypertrophy of mesangial cells. Diabetologia. 2003, 46:1090-1099
8. Vincenzo Scivittard, Michael B. Ganz, and Miriam F. WeissAGEs induce oxidative stress and active protein kinase C- in neonatal mesangial cells. Am J Physiol Renal Physiol. 2000, 278:F676-F683
9. Margo P. Cohen, Fuad N. Ziyaden, Gregory T. Lautenslager, et. al. Glycated albumin stimulation of PKC-β activity is linked to increased collagen IV in mesangial cells. Am. J. Physiol. 1999, 276(Renal Physiol.45):F684-F690
10. Bing-Fen Liu, Satoshi Miyata, Yushi Hirota, et. al. Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells. Kidney International. 2003, 63:947-957
11. Winnie Chan, Kwei Chi Lin, Peck-Sun Lin, et. al. Growth inhibition of rat mesangial cells by high glucose: effect of vitamin E. Clin Exp Nephrol. 1999, 3:268-2711. G.Dogra, G.F.Watts.Genes and diabetic nephropathy: what have we learnt so far? Pract Diab Int.2000, 17(3): 84-90
2. Shinichi Nishi, Mitsuhiro Ueno, Shimada HisakiNoriaki Iino, et. al.Ultrastructural characteristics of diabetic nephropathy. Med Electron Microsc. 2000, 33: 65-73
3. Effie C Tsilibary. Microvascular basement membranes in diabetes mellitus. Journal of Pathology. 2003, 200: 537-546
4. Amanda I.Adler, Richard J.Stevens, Sue E.Manley, et. al.Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney International. 2003, 63: 225-232
5. Ryuichi Kikkawa, Daisuke Koya, and Masakazu Haneda.Progression of diabetic nephropathy. American Journal of Kidney Diseases. 2003, 41(3, Suppl 1): S19-S21
6. Christoph Hasslacher. "Diabetic Nephropathy",. 2001.
7. Giuseppe D'Amico and Claudio Bazzi.Pathophysiology of proteinuria. Kidney International 2003, 63(3): 809-825
8. M.Luiza Caramori, Paola Fioretto, and Michael Mauer. Perspectives in diabetes the need for early predictors of diabetic nephropathy risk is albumin excretion rate sufficient? Diabetes. 2000, 49: 1399-1408
9. Tanya M.Osicka, Yunxia Yu, Sianna Panagiotopoulos.Prevention of albuminuria by??aminoguanidine or ramipril in streptozotocin induced diabetic rats I s associated with the normalization of glomerular protein kinase C. Diabetes. 2000, 49:87-93
10. Eli A.Friedman. Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications. Diabetes Care. 1999, 22(Suppl. 2):B65-B71
11. Michael Brownlee. Advanced protein glycosylation in diabetes and aging. Annu.Rev.Med. 1995, 46:223-234
12. Dominic S.C.Raj, Devasmita Choudhury, Tomas C.Welbourne. Advanced glycation end products: a nephrologist's perspective. American Journal of Kidney Diseases. 2000, 35(3):365-380
13. Katsunori Horie, Toshio Miyata, Kenji Maeda, et. al. Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J.Clin.Invest. 1997, 100:2995-3004
14. E.A.Friedman. Advanced glycation end products in diabetic nephropathy. Nephrol dial transplant. 1999, 14(supple3):1-9
15. August Heidland, Katarina Sebekova, and Reinhard Schinzel. Advanced glycation end products and the progressive course of renal disease. American Journal of Kidney Diseases. 2003, 38(4, Suppl 1):S100-S106
16. Zolta'n Wagner, Istva'n Wittmann, Istva'n Maza'k, et. al. Ne-(carboxymethyl) lysine levels in patients with type 2 diabetes: role of renal function. American Journal of Kidney Diseases. 2003, 38(4):785-791
17. Mark E.Williams. New therapies for advanced glycation end product nephrotoxicity: current challenges. American Journal of Kidney Diseases. 2003, 41(3, Suppl 1):S42-S47
18. Tomonori Uchimura, Kazushi Nakano, Teruto Hashiguchi, et. al. Elevation of N-(carboxymethyl)valine residue in hemoglobin of diabetic patients its role in the development of diabetic nephropathy. Diabetes Care. 2001, 24:891-896
19. Katary(?)na S ebekova, Veronika Faist, Thomas Hofmann, et. al.Effects of a diet rich in advanced glycation end products in the rat remnant kidney model. American Journal of Kidney Diseases. 2003, 41(3, Suppl 1): S48-S51
20. Feng Zheng, Cijiang He, Weijing Cai, et. al. Prevention of diabetic nephropathy in mice by a diet low in glycoxidation products. Diabetes/Metabolism Research and Reviews. 2002,??18:224-237
21. Cijiang He, Jennifer Sabol, Tomoko Mitsuhashi, et. al. Dietary glycotoxins inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration. Diabetes. 1999, 48: 1308-1315
22. I.london O and M.Bendayan. Temporary effects of circulating amadori products on glomerular filtration properties in the normal mouse. Am J Physiol Renal Physiol. 2001, 280:F103-F111
23 D.H.Atchley, M.F.Lopes-Virella 1, D.Zheng, et. al.Oxidized LDL-anti-oxidized LDL immune complexes and diabetic nephropathy. Diabetologia. 2002, 45(11): 1562-1571
24. Marina A.Mironova, Richard L.Klein, Gabriel T. Virella, et.al. Anti-modified LDL antibodies, LDL-containing immune complexes, and susceptibility of LDL to in vitro oxidation in patients with Type 2 diabetes. Diabetes. 2000, 49:1033-1041
25. Xing Yu Wang, Richard Bucala and Ross Miline. Epitopes close to the apolipoprotein B low density lipoprotein receptor-binding site are modified by advanced glycation end products. Proc.Natl.Acad.Sci. 1998, 95:7643-7647
26. Trevor J.Orchard, Gabriel Virella, Kimberly Y.Z.Forrest, et.al Antibodies to oxidized LDL predict coronary artery disease in Type 1 diabetes a nested case-control study from the Pittsburgh epidemiology of diabetes complications study. Diabetes. 1999, 48:1454-1458
27. Rie Shibayama, None Araki, Ryoji Nagai, et.al.Autoantibody against N-(carboxymethyl)lysine an advanced glycation end product of the maillard reaction. Diabetes. 1999, 48:1842-1849
28. Ve'ronique Witko-Sarsat, Miriam Friedlander, Thao Nguyen Khoa, et.al. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure 1. The Journal of Immunology. 1998, 61:2524-2532
29. Caroline Sassy-Prigent, Didier Heudes, Chantal Mandet, et.al. Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes. 2000, 49(3):466-475
30. Richard K.M. Wong, Andrew I. Pettit, Joan E. Davies, et. al. Augmentation of the neutrophil respiratory burst through the action of advanced glycation end products a potential contributor to vascu(?)lar oxidant stress. Diabetes. 2002, 51:2846-2853
31. Peter Reaven, Shiva Merat, Florencia Casanada, et.al. Effect of streptozotocin-induced hyperglycemia on lipid profiles, formation of advanced glycation endproducts in lesions, and??extent of atherosclerosis in LDL receptor-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997, 17:2250-2256
32. Thorsten P.Degenhardt, Nathan L.Alderson, David D.Arrington, et.al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney International. 2002, 61:939-950
33. Joelle M.Onorato, Alicia J.Jenkins, Suzanne R.Thorpe, et.al. Pyridoxamine, an inhibitor of advanced glycation reactions, also Inhibits advanced lipoxidation reactions mechanism of action of pyridoxamine. J Biol Chem. 2000, 275(28):21177-21184
34. Paul A.Voziyan, Thomas O.Metz, John W.Baynes, et. al. A post-amadori inhibitor pyridoxamine also inhibits chemical modification of proteins by scavenging carbonyl intermediates of carbohydrate and lipid degradation. J Biol Chem. 2002, 277(5):3397-3403
35. Ida Giardino, Annan K.Fard, Diane L.Hatchell, et.al. Aminoguanidine inhibits reactive oxygen species formation, lipid peroxidation, and oxidant-induced apoptosis. Diabetes. 1998, 47:1114-1120
36. D.Bonefont-Rousselot, J.P.Bastard, M.C.Jaudon, et.al. Consequences of the diabetic status on the oxidant/antioxidant balance. Diabetes & Metabolism. 2000, 26:163-176
37. Jakus V. The role of free radicals, oxidative stress and antioxidant systems in diabetic vascular disease. Bratisl Lek Listy. 2000, 101(10):541-551
38. Vincenzo Scivittaro, Michael B.Ganz, and Miriam F.Weiss. AGEs induce oxidative stress and activate protein kinase C-bII in neonatal mesangial cells. Am J Physiol Renal Physiol. 2000, 278:F676-F683
39. Daisuke Suzuki, Toshio Miyata, Noboru Saotome, et.al. Immunohistochemical evidence for an increased oxidative stress and carbonyl modification of proteins in diabetic glomerular lesions. J Am Soc Nephrol. 1999, 10:822-832
40. Howard Trachtman, Stephen Futterweit, Elyse PineJared Mann, et. al. Chronic diabetic nephropathy: role of inducible nitric oxide synthase. Pediatr Nephrol. 2002, 17:20-29
41. Roland Veelken, Karl F.Hilgers, Andrea Hartner, et.al. Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy. J Am Soc Nephrol. 2000, 11:71-79
42. T. Soulis 1, M.E. Cooper 1, S. Sastra 1, et. al. Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats.??Diabetologia. 1997, 40: 1141-1151
43. W.Brian Reeves and Thomas E.Andreoli T. Transforming growth factor b contributes to progressive diabetic nephropathy. PNAS. 2000, 97(14):7667-7669
44. Fuad N.Ziyadeh, Brenda B.Hoffman, Dong Cheol Han, et.al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal anti transforming growth factor-b antibody in db/db diabetic mice. PNAS. 2002, 97:8015-8020
45. Darren J.Kelly, Richard E.Gilbert, Alison J.Cox, et.al. Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy. J Am Soc Nephrol. 2001, 12:2098-2107
46. J.W.van der Pijl, M.R.Daha, J.van den Born, et.al. Extracellular matrix in human diabetic nephropathy: reduced expression of heparan sulphate in skin basement membrane. Diabetologia 1998, 41:791-798
47. Giovanni Gambaro and Fokko J.Van Der Woude. Glycosaminoglycans use in treatment of diabetic nephropathy. J Am Soc Nephrol. 2000, 11:359-368
48. Tore Julsrud Berg, Phdper Hilderbrandt. Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes. Diabetes Care. 1999, 22(7):1186-1190
49. Gavin R.Norton, Geoff Candy. Aminoguanidine prevents the decreased myocardial compliance produced by streptozotocin-induced diabetes mellitus in rats. Circulation 1996, 93:1905-1912
50. Mohammad Asif, John Egan, Sara Vasan, et.al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. PNAS. 2000, 97(6):2809-2813
51. Jonathan R. Rumble, Mark E. Cooper, Tina Soulis, et. al. Vascular hypertrophy in experimental diabetes role of advanced glycation end products. J. Clin. Invest. 1997, 99:1016-1027
52. Bruce H.R.Wolffenbuttel, Chantal M.Boulanger, Francy R.L.Crijns. Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc.Natl.Acad.Sci. 1998, 95:4630-4634
53. Bruno Corman, Micheline Duriez, Pierre Poitevin, et.al. Aminoguanidine prevents age-related arterial stiffening and cardiac hypertrophy. PNAS. 1998, 95(3): 1301-130654. Alan Stitt, Thomas A.Gardiner, Nathan L.Anderson, et.al. The AGE Inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes. 2002, 51:2826-2832
55. Mitsushi Inomata, Masami Hayashi, Seigo Shumiya. Aminoguanidine-treatment results in the inhibition of lens opacification and calpain-mediated proteolysis in Shumiya cataract rats (SCR). J.Biochem. 2000, 128: 771-776
56. Timothy S.Kern 1 and Ronald L.Engerman. Pharmacological inhibition of diabetic retinopathy aminoguanidine and aspirin. Diabetes 2001, 50:1636-1642
57. Jennifer L.Wilkinson-Berka, Darren J.Kelly, Suzanne M.Koerner, et.al. ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mREN-2)27 rat. Diabetes. 2002, 51:3283-3289
58. P.H.Yu, D.M.Zuo.Aminoguanidine inhibits semicarbazide-sensitive amine oxidase activity: implications for advanced glycation and diabetic complications. Diabetologia. 1997, 40:1243-1250
59. Leon A.Bach, Rachael Dean, Sherrif Youssef, et. al. Aminoguanidine ameliorates changes in the IGF system in experimental diabetic nephropathy. nephrol dial transplant. 2000, 15:347-354
60. H.Sugimoto 1, K. Shikata 1, J. Wada 1, et. al. Advanced glycation end products- cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-a and inducible nitric oxide synthase in diabetic rat glomeruli. Diabetologia. 1999, 42: 878-886
61. A.Ashley Booth, Raja G. Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glucation end products: comparision of aminoguanidine. Biochemical and biophysical research communications. 1996, 220:113-119
62. Daisuke Koya and George L.King. Perspectives in diabetes protein kinase C activation and the development of diabetic complications. Diabetes. 1998, 47:859-866
63. Katherine R.Tuttle, and Pamela W.Anderson. A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C inhibition. American Journal of Kidney Diseases. 2003, 42(3): 456-465
64. Daisuke Koya, Masakazu Haneda, Hiroko Nakagawa, et.al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC-βinhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. The FASEB Journal. 2000, 14:439-44765. Tina Soulis-Liparota, Mark Cooper, Dimitria Papazoglou. Retardation by amino- guanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes. 1991, 40:1328-13341. Hi Bahl Lee, Hunjoo Ha, Sung Il Kim, and Fuad N.Ziyadeh. Diabetic kidney disease research: Where do we stand at the turn of the century ? Kidney International. 2000, 58(Supp177): S1-S2
2. Dominic S.C.Raj, Devasmita Choudhury, Tomas C.Welboume. et. al. Advanced Glycation End Products: A Nephrologist's Perspective. American Journal of Kidney Disease. 2000, 135: 365-380
3. A.Gugliuccl and T.Menini. Circulating Advanced Glycation Peptides in Streptozotocin induced Diabetic Rats: Evidence for Preferential Modification of IgG Light Chains. Life Science. 1998, 62: 2141-2150
4. R.Singh, A.Barden, T.Mori, L.Beilin. Advanced glycation end products: a review. Diabetologia.2001, 44: 129-146
5. Sherif Youssfe, Dominique T.Nguyen, Tina Soulis, et. al. Effect of diabetes and aminoguanidine therapy on renal advanced glycation end-product binding. Kidney International.1999, 55: 907-916
6. Giuseppe Pugliese, Flavia Pricci, Gaetano Leto, et. al. The Diabetic Milieu Modulates the Advanced Glycation End Product-Receptor Complex in the Mesangium by Inducing or Upregulating Galectin-3 expression. Diabetes. 2000, 49: 1249-1257
7. Nobushige Tanaka, hideto Yonekura, Sho-ichi Yamagishi, et. al. The Receptor for Advanced??Glycation End Products Is Induced by the Glycation Prooducts Themselves and Tumor Necrosis Factor-a through Nuclear Factor-kB, and by 17b-Estrdiol through Sp-1 in Human Vascular Endothelial Cells; The Journal of Biological Chemistry. 2000, 275: 25781-25790
8. Tina Soulis, Mark E.Cooper, Dimitria Vranes, Richard Bucala, et. al. Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment. Kidney International. 1996, 50:627-634
9. Tomoko Shimoike, toyoshi Inoguchi, Fumio Umeda, et. al. The Meaning of Serum Levels of Advanced Glycation End Products in Diabetic Nephropathy. Metabolism. 2000, 49:1030-1035
10. Mark E.Cooper, Richard E.Gilbert, and Murray Epstein. Pathophysiology of Diabetic Nephropathy. Metabolism. 1998, 47(Suppl l):3-6
11. Michael Browniee. Negative Consequences of glycation. Metabolism. 2000, 49(Suppl 1):9-13
12. Verbeke P, Perichon M, Friguet B, Bakala H, et. al. Inhibition of nitric oxide synthase activity by early and advanced glycation end products in cultured rabbit proximal tubular epithelial cells. Biochim Biophys Acta. 2000, 1502(3):481-494
13. Heidland A, Sebekova K, Schinzel R, et. al. Advanced glycation end products and the progressive course of renal disease. Am J Kidney Dis. 2001, 38(4 Suppl 1):S100-106
14. Guangsheng Xiang, Reinhard Schinzei, Andreas Simm, Katarina Sebekova, et. al. Advanced glycation end products impair protein turnover in LLC-PK1: Ame- lioration by trypsin. Kidney International. 2001, 59(Suppl.78): S-53-S-57
15. Iwashima Y, Eto M, Horiuchi S, Sano H, et. al. Advanced glycation end product-induced peroxisome proliferator-activated re- ceptor gamma gene expression in the cultured mesangial cells. Biochem Biophys Res Commun. 1999, 264(2):441-8
16. Mene P, Pascale C, Teti A, Bernardini S, et. al. Effects of advanced glycation end products on cytosolic Ca2 signaling of cultured human mesangial cells. J Am Soc Nephrol. 1999, 10:1478-1486
17. Deng Y, Chen X, Ye Y. Effects of glycated protein on the expression of plasminogen activator inhibitor-1 of cultured human mesangial cells. NATIONAL MEDICAL JOURNAL OF CHINA 1997, 77(9):672-675
18. Pugliese G, Pricci F, Romeo G, et. al. Upregulation of mesangial growth factor and extracellular matrix synthesis by advanced glycation end products via a receptor-mediated??mechanism. Diabetes. 1997, 46: 1881-1887
19. Iehara N, Takeoka H, Yamada Y, et. al. Advanced glycation end products modulate transcriptional regulation in mesangial cells. Kidney Int. 1996, 50: 1166-1172
20. Throckmorton DC, Brogden AP, Min B, Rasmussen H, et. al. PDGF and TGF-beta mediate collagen production by mesangial cells exposed to advanced glycosylation end products. Kidney Int. 1995, 48: 111-117
21. Kim YS, Kim BC, Song CY, et. al. Advanced glycosylation end products stimulate collagen mRNA synthesis in me-sangial ceils mediated by protein kinase C and transforming growth factor-beta. J Lab Clin Med. 2001, 138: 59-68
22. Patrizo R Oddetti, Antonella Borgoglio, Angelo De Pascale, et. al. Prevention of Diabetes-increased Aging Effect on Rat Collagen-linked Fluores-cence by Aminoguanidine and Rutin. Diabetes. 1990, 39: 796-801
23. Winnie Deuther-Conrad, Sybille Franke, Manfred Sommer, et. al. Difference in the modulating potential of advanced glycation end product (age) peptides versus AGE proteins. Kidney International. 2001, 59(Supp178): S-63-S-66
24. Suree Jianmongkol, Jennifer L. Vuletich, Andrew T. Bender, et. al. Aminoguanidine mediated Inactivation and Alteration of Neuronal Nitric-oxide Synthase. The Journal of Biological Chemistry. 2000, 275: 13370-13376
25. T.Soulis, M.E.Cooper, S.Satra, et. al. Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediaed renoprotection in diabetic rats. Diabetologia.1997, 40: 1141-1151.
26. B.O.Nilsson. Biological efects of aminoguanidine: An update. Inflammation Research. 1999, 48: 509-515
27. M.S.P.huijberts, B.H.R.Wolffenbuttel, F.R.L.Crijns, et. al. Aminoguanidine reduces regional albumin clearance but not urinary albumin excretion in streptozotocin-diabetic rats. Diabetologia. 1994, 37: 10-14.
28. TanyaM.Osicka, YunxiaYu, Sianna Panagiotopoulos, et. al. Prevention of Albuminuria by Aminoguanidine or Ramiprilin Streptozotocin-induced Diabetic Rats Is Associated With the Normalization of Glomerular Protein Kinase C. Diabetes. 2000, 49: 87-93
29. Tina Soulis-liparota, Mark Cooper, Dimitria Papazoglou, et. al. Retardation by??Aminoguanidine of Development of Albuminuria, Mesangial Expansion, and Tissue Fluorescence in Streptozocin-induced Diabetic Rat. Diabetes. 1991, 40:1328-1334
30. Leon A.Bach, Rachael Dean, Shrrif Youssef, et. al. Aminoguanidine ameliorates changes in the IGF system in experimental diabetic nephropathy. Nephrol Dial Transplant. 2000, 15:347-354
31. Sung-Hee Ihm, Hyung Joon Yoo, Sung Woo Park, et. al. Effect of Aminoguanidine on Lipid Peroxidation in Streptozotocin-Induced Diabetic Rats. Metabolism. 1999, 48:1141-1145
32. Shinsuke Hiramatsu, Kauru Inoue, Yuji Tajirl, et. al. Impovement by Aminoguanidine of Insulin Secretion from Pancreatic Islets Grafted to Syngeneic Diabetic Rats. Biochemical Pharmacology. 2000, 60:263-268
33. Paulina Sannomiya, Maria Aoliveira & Zuleica B. Fortes. Aminoguanidine and the prevention of leukocyte dysfunction in diabetes mellitus: a direct vital microscopic study. British Journal of Pharmacology. 1997, 122:894-898
34. J.M.Forbes, T.Soulis, V.Thallas, et. al. Renoprotective effects of a novel inhibitor of advanced glycation. Diabetologia. 2001, 44:108-114
35. Peter S. Oturai, Mogens Christensen, Bidda Rolin, et. al. Effects of Advanced Glycation End-Product Inhibition and Cross-Link Breakage in Diabetic Rats. Metabolism. 2000, 49(8):996-1000
36. Seikoh Horiuchi, None Araki, and Yoshimasa Morino. Immunochemical Approach to Characterize Advanced Glycation End Products of the Maillard Reaction. The Jounal of Biological Chemistry. 1991, 266:7329-7332
37. Rie Shibayama, None Araki, Ryoji nagai, et. al. Autoantibody against N~ε-(carboxymethyl)lysine an advanced glycation end pro- duct of the maillard reaction. Diabetes. 1999, 48: 1842-1849
38. Katarina Sebekova, Pavol Blazicer, Dagmar Syrova, et. al. Circulating advanced glycation end product levels in rats rapidly increase with acute renal failure. Kidney International. 2001, 59(Suppl.78):S-58-S-62
39. Toshio Miyata, Satoshi Sugiyama, Akira Saito, et. al. Reactive carbonyl compounds related uremic toxicity ("carbonyl stress"). Kidney International. 2001, 59(Suppl.78):S-25-S-31