Summary
Diabetic late complications are characterized by morphological and biochemical alterations of the extracellular matrix. In particular, longstanding diabetes causes quantitative and qualitative changes in basement membrane structure of retinal and renal capilleries. Immunohistochemical investigations of diabetic kidneys with diffuse glomerulosclerosis show increased collagen type IV deposition in the mesangial matrix and decreased heparan sulfate proteoglycan content in the mesangial matrix and glomerular basement membrane as well. In nodular glomerulosclerosis normal basement membrane components are decreased or absent while the occurrence of collagen type III in this stage has been interpreted as an irreversible alteration of the glomerular structure. These changes seem to be the underlying cause for the alterations in renal functions like persistent albuminuria and proteinuria. Increased intra- and extracellular levels of glucose and its derivatives are thought to be responsible for diabetic tissue dysfunction although there are reports on possible genetic defects causing increased susceptibility to develop diabetic nephropathy. Recent results, however, focuse on the role of glucose-induced cytokine secretion as mediator for altered metabolism of glomerular matrix proteins. In vitro studies with cultured kidney cells have shown that the glucose-induced dysregulation of the basement membrane synthesis may be mediated by a glucose dependent activation of protein kinase C. Alternatively or synergistically, the formation of AGE products formed after prolonged exposure of matrix proteins to elevated glucose may also lead to cytokine secretion subsequently inducing synthesis of extracellular matrix proteins. Studies in experimental animals confirm the diabetes induced dysregulation of the synthesis of extracellular matrix components on the molecular level.
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Abbreviations
- HSPG:
-
heparan sulfate proteoglycan
- GBM:
-
glomerular basement membrane
- ECM:
-
extracellular matrix
- AGE:
-
advanced glucosylation end products
- TNF:
-
tumor necrosis factor
- bFGF:
-
basic fibroblast growth factor
References
Ayo SH, Radnik R, Garoni JA, Troyer DA, Kreisberg JA (1991) High glucose increases diacylglycerol mass and activates protein kinase C in mesangial cells. Am J Physiol 261: F571–577
Ayo SH, Radnik RA, Glass IIWF, Garoni JA, Rampt ER, Appling DR, Kreisberg JI (1990) Increased extracellular matrix synthesis and mRNA in mesangial cells grown in high-glucose medium. Am J Phys 260: F185-F191
Brownlee M, Cerami A, Vlassara H (1988) Advanced glucosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318:1315–21
Cagliero E, Maiello M, Boeri D, Roy S, Lorenzi M (1988) Increased expression of basement membrane components in human endothelial cells cultured in high glucose. J Clin Invest 82:735–738
Deckert T, Horowitz IM, Kofoed-Enevoldsen Kjellen L, Deckert M, Lykkelund C, Burcharth F (1991) Possible genetic defects in regulation of glycosaminoglycans in patients with diabetic nephropathy. Diabetes 40:764–770
Doi T, Vlassara H, Kirstein M, Yamada Y, Striker GE, Striker LJ (1992) 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 89:2873–2877
d'Amore PA (1990) Modes of FGF release in vivo and in vitro Cancer and Metastasis Reviews 9:227–238
Farquhar MG (1981) The glomerular basement membrane: a selective macromolecular filter. In: E Hay (ed) Cell biology of extracellular matrix. Plenum Press New York, London, pp 335–378
Fukui M, Nakamura T, Ebihara I, Shirato I, Tomino Y, Koide H (1992) ECM gene expression and its modulation by insulin in diabetic rats. Diabetes 41:1520–1527
Greene D (1988) The pathogenesis and its prevention of diabetic neuropathy and nephropathy. Metabol 37 [Suppl] 1:25–29
Guzman NJ, Crews FT (1992) Regulation of inositol transport by glucose and protein kinase C in mesangial cells. Kidney Int 42:33–40
Haneda M, Kikkawa R, Horide N, Togawa M, Koya D, Kajiwara N, Ooshima A, Shigeta Y (1991) Glucose enhances type IV collagen production in cultured rat glomerular mesangial cells. Diabetologia 34:198–200
Kallunki P, Tryggvason K (1992) Human basement membrane heparan sulfate proteoglycan core protein: a 467-kD protein containing multiple domains resembling elements of the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor. J Cell Biol 116:559–71
Kern TS, Engerman TL (1990) Arrest of glomerulopathy in diabetic dogs by improved diabetic control. Diabetologia 21:178–83
Kim Y, Kleppel M, Butkowski R, Mauer M, Wieslander J, Michael A (1991) Differential expression of basement membrane collagen chains in diabetic nephropathy. Am J Pathol 138:413–420
Kimmelstiel P, Wilson C (1936) Intercapillary lesions in the glomeruli of the kidney. Am J Pathol 12:83–89
Larkins RG, Dunlop ME (1992) The link between hyperglycaemia and diabetic nephropathy. Diabetologia 35:499–504
Ledbetter SR, Copeland EJ, Noonan D, Vogeli G, Hassel JR (1990) Altered steady-state in mRNA levels of basement membrane proteins in diabetic mouse kidneys and thromboxane synthase inhibition. Diabetes 39:196–203
Ledbetter SR, Wagner CW, Martin GR, Rohrbach DH, Hassell JR (1987) Response of diabetic basement membrane-producing cells to glucose and insulin. Diabetes 36:1029–1034
Ledl F, Schleicher E (1990) New aspects of the Maillard reaction in foods and in the human body. Angew Chem Int Ed Engl 29:565–594
Li W, Chan LS, Khatami M, Rockey JH (1986) Non-competitive inhibition of myo-inositol transport in cultured bovine retinal capillary pericytes by glucose and reversal by sorbinil. Biochem Biophys Acta 857:198–208
McCaleb ML,Mc Kean ML, Hohman TC, Laver N, Robinson WG (1991) Intervention with aldose reductase inhibitor, tolrestat, in renal and retinal lesions of streptozotocin diabetic rats. Diabetologia 34:659–701
McClain DA, Paterson AJ, Roos MD, Wei X, Kudlow JE (1992) Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells. Proc Natl Acad Sci USA 89:8150–8154
Nerlich A, Schleicher E (1991) Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions. Am J Pathol 139:889–899
Olgemöller B, Schleicher E (1993) Veränderung der Basalmembranen als biochemisches Korrelat der diabetischen Spätschäden. Diabetes und Stoffwechsel 1: (in press)
Olgemöller B, Schleicher E, Nerlich A, Wagner E, Gerbitz KD (1990) Isolation, characterization and immunological determination of basement membrane-associated heparan sulfate proteoglycan. Biol Chem Hoppe Seyler 370:1321–1329.
Olgemöller B, Schleicher E, Schwaabe S, Gerbitz KD (1992) Upregulation of myo-inositol transport compensates for competitive inhibition by glucose Diabetes (in press)
Olgemöller B, Schwaabe S, Gerbitz KD, Schleicher ED (1992) Elevated glucose decreases the content of a basement membrane associated proteoglycan in proliferating mesangial cells. Diabetologia 35:183–186
Olgemöller B, Schwaabe S, Schleicher ED, Gerbitz KD (1990) Competitive inhibition by glucose of myo-inositol incorporation into cultured porcine mesangial cells. Biophys Biochem Acta 1052:47–52
Rohrbach DH, Hassell JR, Kleinman HK, Martin GR (1982) Alterations in the basement membrane (heparan sulphate) proteoglycan in diabetic mice. Diabetes 31:185–188
Ruoslahti E (1990) Extracellular matrix in the regulation of cellular functions. In: Burger MM, Sordat B, Zinkernagel RM (eds) Cell to cell interaction. Karger, Basel
Schaefer RM, Paczek L, Huang S, Teschner M, Schaefer L, Heidland A (1992) Role of glomerular proteinases in the evolaution of glomerulosclerosis. Eur J Clin Chem Clin Biochem 30:641–646
Schleicher E, Wieland OH (1984) Changes of human glomerular basement membrane in diabetes mellitus. Eur J Clin Chem Clin Biochem 22:223–227
Schleicher ED, Wagner EM, Olgemöller B, Nerlich AG, Gerbitz KD (1989) Characterization and localization of basement membrane-associated heparan sulphate proteoglycan in human tissues. Lab Invest 61:323–332
Schmolke M, Schleicher E, Guder WG (1992) Renal sorbitol, myo-inositol and glycerophosphorylcholine in streptozotocin-diabetic rats. Eur J Clin Chem Clin Biochem 30:607–614
Shimomura H, Spiro RG (1987) Studies on macromolecular components of human glomerular basement membrane and alterations in diabetes: decreased levels of heparan sulfate proteoglycan. Diabetes 36:374–81
Steffens MW, Osterby R, Chavers B, Mauer, MS (1989) Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients. Diabetes 38:1077–81
Stow JL, Sawada H, Farquhar MG (1985) Basement membrane heparan sulfate proteoglycans are concentrated in the laminae rarae and in podocytes of the rat renal glomerulus. Proc Natl Acad Sci USA 82:3296–3300
Timpl R (1989) Structure and biological activity of basement membrane proteins. Eur J Biochem 180:487–503
Unger E, Pettersson I, Eriksson UJ, Lindahl U, Kjellen L (1991) Decreased activity of the heparan sulfate-modifying enzyme glucosaminyl N-deacetylase in hepatocytes from streptozotocin-diabetic rats. J Biol Chem 266:8671–8674
van den Born J, van den Heuvel PWJ, Bakker MAH, Veerkamp JH, Assmann KJM, Berden JHM (1992) A monoclonal antibody against GBM heparan sulfate induces an acute selective proteinuria in rats. Kidney Int 41:115–123
Vlassara H, Brownlee M, Cerami A (1986) Noval macrophage receptor for glucose-modified proteins is distinct from previously described scavenger receptors. J Exp Med 164:1301–1309
Vogt BW, Schleicher ED, Wieland OH (1982) ɛ-aminolysine bound glucose in human tissues obtained at autopsy: increase in diabetes mellitus. Diabetes 31:1123–1127
Wolf G, Sharma K, Chen Y, Ericksen M, Ziyadeh FN (1992) High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-β. Kidney Int 42:647–656
Wright TC, Casellot JJ, Diamond JR, Karnovsky MJ (1989) Regulation of cellular proliferation by heparin and heparan sulfate. In: Lane DA, Lindahl U (eds) Heparin. Edward Arnold, London, pp 295–316
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Olgemöller, B., Schleicher, E. Alterations of glomerular matrix proteins in the pathogenesis of diabetic nephropathy. Clin Investig 71, S13–S19 (1993). https://doi.org/10.1007/BF00180071
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DOI: https://doi.org/10.1007/BF00180071