Increases in extracellular matrix (ECM) and changes in its components have been documented in the glomeruli of diabetic nephropathy. Advanced glycation end products formed by glycoxidation have been shown to induce the synthesis of ECM components and transforming growth factor beta (TGF-β), suggesting that advanced glycation end products may be involved in the etiology of imbalance of ECM components in diabetic glomerulosclerosis. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an inbred strain that spontaneously develops non-insulin-dependent diabetes mellitus which progresses to diabetic glomerulosclerosis. NΕ-(carboxymethyl)lysine (CML) is known to be formed by glycoxidation. To clarify the involvement of glycoxidation in diabetic nephropathy, we examined the localization of CML, ECM components, and TGF-β1 in the glomeruli of OLETF rats. The amounts of α3(IV) collagen, type VI collagen, and fibronectin were significantly increased in the glomeruli of OLETF rats, whereas the heparan sulfate proteoglycan levels were decreased. After 6 months of age, CML levels were significantly increased in the mesangial area of the glomeruli in these animals. The overexpression of TGF-β1 preceded the increase in glomerular ECM components. The present study demonstrated that the accumulation of CML precedes the changes of glomerular ECM components in the glomeruli during the course of diabetic nephropathy, suggesting that glycoxidation may be one of the major causes of diabetic glomerulosclerosis.

Keywords:
Diabetic nephropathy, OLETF rat, Advanced glycation end products, Nε-(Carboxymethyl)lysine, Extracellular matrix, Transforming growth factor beta, Collagen
1.
Makino H, Yamasaki Y, Haramoto T, Shikata K, Hironaka K, Ota Z, Kanwar YS: Ultrastructural changes of extracellular matrices in diabetic nephropathy revealed by high resolution scanning and immunoelectron microscopy. Lab Invest 1993;68:45–55.
2.
Ziyadeh FN: The extracellular matrix in diabetic nephropathy. Am J Kidney Dis 1993;22:736–744.
3.
Davies M, Martin J, Thomas GJ, Lovett DH: Proteinases and glomerular matrix turnover. Kidney Int 1992;41:671–678.
4.
Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA: Expression of transforming growth factor β is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci USA 1993;90:1814–1818.
5.
Maillard LC: Actions des acides aminés sur les sucres: formation des mélanoïdines par voie méthodique. C R Hebd Séanc Acad Sci 1912;154:66–68.
6.
Rahbar S: An abnormal hemoglobin in red cells of diabetics. Clin Chim Acta 1968;22:296–298.
7.
Day JF, Thorpe SR, Baynes JW: Nonenzymatically glucosylated albumin: In vitro preparation and isolation from normal human serum. J Biol Chem 1979;254:595–597.
8.
Vlassara H, Bucala R, Striker L: Pathogenic effects of advanced glycosylation: Biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest 1994;70:138–151.
9.
Brownlee M, Vlassara H, Cerami A: Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann Intern Med 1984;101:527–537.
10.
Monnier VM, Vishwanath V, Frank KE, Elmets CA, Dauchot P, Kohn RR: Relation between complications of type I diabetes mellitus and collagen-linked fluorescence. N Engl J Med 1986;314:403–408.
11.
Brownlee M, Cerami A, Vlassara H: Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988;318:1315–1321.
12.
Schnider SL, Kohn RR: Effects of age and diabetes mellitus on the solubility and nonenzymatic glucosylation of human skin collagen. J Clin Invest 1981;67:1630–1635.
13.
Monnier VM, Kohn RR, Cerami A: Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci USA 1984;81:583–587.
14.
Monnier VM, Cerami A: Nonenzymatic browning in vivo: Possible process for aging of long-lived proteins. Science 1981;211:491–493.
15.
Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T: Spontaneous long- term hyperglycemic rat with diabetic complications, Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 1992;41:1422–1428.
16.
Kawano K, Hirashima T, Mori S, Natori T: OLETF (Otsuka Long-Evans Tokushima Fatty) rat: A new NIDDM rat strain. Diabetes Res Clin Pract 1994;24(suppl):317–320.
17.
Sato T, Asahi Y, Toide K, Nakayama N: Insulin resistance in skeletal muscle of the male Otsuka Long-Evans Tokushima Fatty rat, a new model of NIDDM. Diabetologia 1995;38:1033–1041.
18.
Zhu M, Noma Y, Mizuno A, Sano T, Shima K: Poor capacity for proliferation of pancreatic beta-cells in Otsuka Long-Evans-Tokushima Fatty rat: A model of spontaneous NIDDM. Diabetes 1996;45:941–946.
19.
Fukuzawa Y, Watanabe Y, Inaguma D, Hotta N: Evaluation of glomerular lesion and abnormal urinary findings in OLETF rats resulting from a long-term diabetic state. J Lab Clin Med 1996;128:568–578.
20.
Makino H, Kashihara N, Sugiyama H, Kanao K, Sekikawa T, Okamato K, Maeshima Y, Ota Z, Nagai R: Phenotypic modulation of the mesangium reflected by contractile proteins in diabetes. Diabetes 1996;45:488–495.
21.
Kim Y, Kleppel MM, Butkowski R, Mauer SM, Wieslander J, Michael AF: Differential expression of basement membrane collagen chains in diabetic nephropathy. Am J Pathol 1991;138:413–420.
22.
Makino H, Gibbons JT, Reddy MK, Kanwar YS: Nephritogenicity of antibodies to proteoglycans of the glomerular basement membrane-1. J Clin Invest 1986;77:142–156.
23.
Horiuchi S, Araki N, Morino Y: Immunochemical approach to characterize advanced glycation end products of the Maillard reaction. J Biol Chem 1991;266:7329–7332.
24.
Ikeda K, Higashi T, Sano H, Jinnouchi Y, Yoshida M, Araki T, Ueda S, Horiuchi S: Nσ-(carboxymethyl) lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction. Biochemistry 1996;35:8075–8083.
25.
Ahmed MU, Dunn JA, Walla MD, Thorpe SR, Baynes JW: Oxidative degradation of glucose adducts to protein: Formation of 3-(N epsilon-lysino)-lactic acid from model compounds and glycated proteins. J Biol Chem 1988;263:8816–8821.
26.
Cervantes-Laurean D, Jacobson EL, Jacobson MK: Glycation and glycoxidation of histones by ADP-ribose. J Biol Chem 1996;271:10461–10469.
27.
Doi T, Vlassara H, Kirstein M, Yamada Y, Striker GE, Striker LJ: Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc Natl Acad Sci USA 1992;89:2873–2877.
28.
Yang CW, Vlassara H, Peten EP, He CJ, Striker GE, Striker LJ: Advanced glycosylation end products upregulate gene expression found in diabetic glomerular disease. Proc Natl Acad Sci USA 1994;91:9436–9440.
29.
Higashi T, Sano H, Saishoji T, Ikeda K, Jinnouchi Y, Kanzaki T, Morisaki N, Rauvala H, Shichiri M, Horiuchi S: The receptor for advanced glycation end products mediates the chemotaxis of rabbit smooth muscle cells. Diabetes 1997;46:463–472.
30.
Timpl R, Wiedemann H, Van Delden V, Furthmayr H, Kühn K: A network model for the organization of type IV collagen molecules in basement membranes. Eur J Biochem 1981;120:203–211.
31.
Shikata K, Makino H, Ota Z: High resolution three-dimensional meshwork structure of the glomerular basement membrane. Jpn J Nephrol 1992;34:379–385.
32.
Makino H, Shikata K, Wieslander J, Wada J, Kashihara N, Yoshioka K, Ota Z: Localization of fibril/microfibril and basement membrane collagens in diabetic glomerulosclerosis in type 2 diabetes. Diabetic Med 1994;11:304–311.
33.
Makino H, Ikeda S, Haramoto T, Ota Z: Heparan sulfate proteoglycans are lost in patients with diabetic nephropathy. Nephron 1992;61:415–421.
34.
Nerlich A, Schleicher E: Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions. Am J Pathol 1991;139:889–899.
35.
Ikeda S, Makino H, Haramoto T, Shikata K, Kumagai I, Ota Z: Changes in glomerular extracellular matrices components in diabetic nephropathy. J Diabet Complications 1991;5:186–188.
36.
Shimomura H, Spiro RG: Studies on macromolecular components of human glomerular basement membrane and alterations in diabetes: Decreased levels of heparan sulfate proteoglycan and laminin. Diabetes 1987:36:374–381.
37.
Templeton DM: Retention of glomerular basement membrane proteoglycans accompanying loss of anionic site staining in experimental diabetes. Lab Invest 1989;61:202–211.
38.
Kashihara N, Watanabe Y, Makino H, Wallner EI, Kanwar YS: Selective decreased de novo synthesis of glomerular proteoglycans under the influence of reactive oxygen species. Proc Natl Acad Sci USA 1992;89:6309–6313.
39.
Kanwar YS, Linker A, Farquhar MG: Increased permeability of the glomerular basement membrane to ferritin after removal of glycosaminoglycans (heparan sulfate) by enzyme digestion. J Cell Biol 1980;86:688–693.
40.
Striker LM-M, Killen PD, Chi E, Striker GE: The composition of glomerulosclerosis. I. Studies in focal sclerosis, crescentic glomerulonephritis, and membranoproliferative glomerulonephritis. Lab Invest 1984;51:181–192.
41.
Abrass CK, Peterson CV, Raugi GJ: Phenotypic expression of collagen types in mesangial matrix of diabetic and nondiabetic rats. Diabetes 1988;37:1695–1702.
42.
Mohan PS, Carter WG, Spiro RG: Occurrence of type VI collagen in extracellular matrix of renal glomeruli and its increase in diabetes. Diabetes 1990;39:31–37.
43.
Wolf G, Sharma K, Chen Y, Ericksen M, Ziyadeh FN: High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-β. Kidney Int 1992;42:647–656.
44.
Nakamura T, Miller D, Ruoslahti E, Border WA: Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-β1. Kidney Int 1992;41:1213–1221.
45.
Bollineni JS, Reddi AS: Transforming growth factor-β1 enhances glomerular collagen synthesis in diabetic rats. Diabetes 1993;42:1673–1677.
46.
Throckmorton DC, Brogden AP, Min B, Rasmussen H, Kashgarian M: PDGF and TGF-β mediate collagen production by mesangial cells exposed to advanced glycosylation end products. Kidney Int 1995;48:111–117.
47.
Sporn MB, Roberts AB, Wakefield LM, de Crombrugghe B: Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol 1987;105:1039–1045.
48.
Sporn MB, Roberts AB: Transforming growth factor β: Multiple actions and potential clinical applications. JAMA 1989;262:938–941.
1998
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