Summary
Diabetic nephropathy is characterized by albuminuria which proceeds to overt proteinuria. The highly negatively stained HS side chain of heparan sulphate proteoglycan (HSPG) is a major determinant of the charge-dependent permeability of the GBM. We set out to study the presence of HS and HSPG in the GBM of patients with diabetic nephropathy using newly developed monoclonal antibodies, and to compare HSPG expression to the expression of other previously investigated glomerular extracellular matrix compounds. Immunohistochemically, glomerular extracellular matrix components were analysed in 14 renal biopsies of patients with diabetic nephropathy and compared with those of normal control subjects. Monoclonal antibodies used were: JM403 against the HS side chain of GBM HSPG and JM72 against the HSPG-core protein. Also, a polyclonal antiserum (B31) against human GBM-HSPG-core protein was used. Additionally, antibodies were used against collagen types I, III, IV and against α1(IV)NC, α3(IV)NC and fibronectin. Staining was scored for intensity and for staining pattern by four independent observers who had no previous knowledge of the sample origin. No glomerular staining was seen for collagen type I. Collagen type III was present in some diabetic nodules. Anti-collagen type IV showed a decreased GBM staining in patients with diabetic nephropathy (p = 0.04). With anti-α1(IV)NC no changes in GBM staining intensity were observed; with anti-α3(IV)NC brilliant GBM staining was seen in both groups. Increased mesangial staining (p = 0.003) was seen with anti-collagen type IV in biopsies with nodular lesions. No differences were observed for fibronectin although it was abundantly present in the mesangial area of biopsies from patients with diabetic nephropathy. In biopsies with mesangial expansion and in biopsies with diabetic nodules, we observed a decreased GBM (p = 0.001) HS side chain staining (JM403) without changes in HSPG-core protein staining (JM72,B31). The HS staining pattern regularly changed from a linear to a more granular and irregular pattern. In patients with a creatinine clearance of more than 15 ml/min, the intensity of GBM HS staining showed an inverse correlation with the rate of proteinuria (r = -0.85, p = 0.004), suggesting a functional relationship. The decreased HS staining in the GBM may reflect the potentially disrupted charge barrier in diabetic nephropathy.
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Abbreviations
- HS:
-
Heparan sulphate
- GBM:
-
glomerular basement membrane
- HSPG:
-
heparan sulphate proteoglycan
- NC:
-
noncollagenous globular domain
- IDDM:
-
insulin-dependent diabetes mellitus
- NIDDM:
-
non-insulin-dependent diabetes mellitus
References
Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A (1989) Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 32: 219–226
Kanwar YS, Rosenzweig LJ, Linker A, Jakubowski ML (1983) Decreased de novo synthesis of glomerular proteoglycans in diabetes: biochemical and autoradiographic evidence. Proc Natl Acad Sci USA 80: 2272–2275
Parthasarathy N, Spiro RG (1982) Effect of diabetes on the glycosaminoglycan component of the human glomerular basement membrane. Diabetes 31: 738–741
Cohen MP, Sarma MC (1981) (35S) Sulphate incorporation into glomerular basement membrane glycosaminoglycan is decreased in experimental diabetes. J Lab Clin Med 98: 715–722
Brown DM, Klein DJ, Michael AF, Oegema TR (1982) 35Sglycosaminoglycan and 35S-glycopeptide metabolism by diabetic glomeruli and aorta. Diabetes 31: 418–425
Kanwar YS, Rosenzweig LJ, Linker A (1983) Decreased de novo synthesis of glomerular proteoglycan in diabetes: biochemical and autoradiographic evidence. Proc Nat Acad Sci USA 80: 2272–2275
Rohrbach DH, Wagner CW, Star VL, Martin GR, Brown KS (1983) Reduced synthesis of basement membrane heparan sulphate proteoglycan in streptozotocin-induced diabetic mice. J Biol Chem 258: 11672–11677
Rohrbach DH, Hasell JR, Kleinman HK, Martin GR (1982) Alterations in the basement membrane (heparan sulphate) proteoglycan in diabetic mice. Diabetes 31: 185–188
Wu VY, Wilson B, Cohen MP (1987) Disturbances in glomerular basement membrane glycosaminoglycans in experimental diabetes. Diabetes 36: 679–683
Klein D, Oegema TR, Brown DM (1989) Release of glomerular heparan-35SO4 proteoglycan by heparin from glomeruli of streptozotocin-induced diabetic rats. Diabetes 38: 1130–1139
Vernier RL, Steffes MW, Sisson-Ross S, Mauer SM (1992) Heparan sulphate proteoglycan in the glomerular basement membrane in type 1 diabetes mellitus. Kidney Int 41: 1070–1080
Edge ASB, Spiro RG (1990) Characterization of novel sequences containing 3-O-sulphated glucosamine in glomerular basement membrane heparan sulphate and localization of sulphated disaccharides to a peripheral domain. J Biol Chem 265: 15874–15881
Rosenzweig LJ, Kanwar YS (1982) Removal of sulphated (heparan sulphate) or non sulphated (hyaluron acid) glycosaminoglycans results in increased permeability of the glomerular basement membrane to 125I albumin. Lab Invest 47: 177–184
Kanwar YS, Linker A, Farquhar MG (1980) Increased permeability of the glomerular basement membrane to ferritine after removal of glycosaminoglycans (heparan sulphate) by enzyme digestion. J Cell Biol 86: 688–693
Groggel GC, Marinides GN, Hovingh P, Hammond E, Linker A (1990) Inhibition of rat mesangial cell growth by heparan sulphate. Am J Physiol 258: F259-F265
Castellot JJ, Hoover RL, Harper PA, Karnovsky MJ (1985) Heparin and glomerular epithelial cell-secreted heparin-like species inhibit mesangial-cell proliferation. Am J Path 120: 427–435
Born J vann den, Heuvel LPWJ, Bakker MAH, Veerkamp JH, Assmann KJM, Berden JHM (1992) A monoclonal antibody against GBM heparan sulphate induces an acute selective proteinuria in rats. Kidney Int 41: 115–123
Born J van den, Heuvel LPWJ van den, Bakker MAH et al. (1993) Evaluation of the distribution of GBM heparan sulphate proteoglycan core protein and side chains in human glomerular diseases by monoclonal antibodies. Kidney Int 43
Fajans SS (1990) Classification and diagnosis of diabetes. In: Rifkin H, Porte D Jr (eds) Diabetes mellitus: theory and practice. Elsevier, New York, pp 346–356
Østerby R, Parving H-H, Nyberg G et al. (1988) A strong correlation between glomerular filtration rate and filtration surface in diabetic nephropathy. Diabetologia 31: 265–270
Harris RD, Steffes MW, Bilous RW, Sutherland DER, Mauer M (1991) Global glomerular sclerosis and glomerular arteriolar hyalinosis in insulin dependent diabetes. Kidney Int 40: 107–114
Van den Heuvel LPWJ, Van den Born J, Van de Velden TJAM et al. (1989) Isolation and partial characterization of heparan sulphate proteoglycan from the human glomerular basement membrane. Biochem J 264: 457–465
Bergijk EC, Munaut C, Baelde JJ et al. (1992) A histological study of the extracellular matrix during the development of glomerulosclerosis in murine chronic graft-versus-host disease. Am J Path 140: 1147–1156
Johansson C, Butkowski R, Wieslander J (1991) Characterization of monoclonal antibodies to the globular domain of collagen IV. Connect Tissue Res 25: 229–241
Parving HH, Gall MA, Skøtt P et al. (1992) Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. Kidney Int 41: 758–762
Brownlee M (1990) Advanced products of nonenzymatic glycosylation and the pathogenesis of diabetic complications. In: Rifkin H, Porte D Jr (eds) Diabetes mellitus: theory and practice. Elsevier, New York, pp 279–291
Suzuki Y (1989) Constituents of the extracellular matrices in diabetic glomerulosclerosis. Jap J Nephr 31: 47–54
Nerlich A, Schleicher E (1991) Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions. Am J Path 139: 889–899
Moran A, Brown DM, Kim Y, Klein DJ (1991) Effects of IGF-1 and glucose on protein and proteoglycan synthesis by human fetal mesangial cells in culture. Diabetes 40: 1346–1354
Mogensen CE (1988) Definition of diabetic renal disease in insulin-dependent diabetes mellitus based on renal function test. In: Mogensen CE (ed) The kidney and hypertension in diabetes mellitus. Martinus Nijhoff Publishing, Boston, pp 7–16
Viberti GC, Jarrett RJ, Mahmud U, Hill RD, Argyropoulos A, Keen H (1982) Microalbuminuria as a predictor of clinical nephropathy in insulin dependent diabetes mellitus. Lancet I: 1430–1432
Mogensen CE, Christensen CK (1984) Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 311: 89–93
Mathiesen ER, Oxenbøll B, Johansen K, Svendsen PA, Deckert T (1984) Incipient nephropathy in type 1 (insulin-dependent) diabetes. Diabetologia 26: 406–410
Mauer SM, Steffes MW, Ellis EN, Sutherland DER, Brown DM, Goetz FC (1984) Structural-functional relationships in diabetic nephropathy. J Clin Invest 74: 1143–1155
Deckert T, Feldt-Rasmussen B, Mathiesen ER (1984) Pathogenesis of diabetic nephropathy: a hypothesis. Diabetic Nephropathy 3: 83–88
Gambaro G, Cavazzana AO, Luzi P et al. (1992) Glycosaminoglycans prevent morphological renal alterations and albuminuria in diabetic rats. Kidney Int 42: 285–291
Shimomura H, Spiro RG (1987) Studies on macromolecular components of human glomerular basement membrane and alterations in diabetes. Diabetes 36: 1374–1381
Falk RJ, Scheinman JI, Mauer SM, Michael AF (1983) Polyantigenic expansion of basement membrane constituents in diabetic nephropathy. Diabetes 32 [Suppl 2]: 34–39
Kim Y, Kleppel MM, Butkowski R, Mauer SM, Wieslander J, Michael AF (1991) Differential expression of basement membrane collagen chains in diabetic nephropathy. Am J Path 138: 413–420
Abrass CK, Peterson CV, Raugi GJ (1988) Phenotypic expression of collagen types in mesangial matrix of diabetic and nondiabetic rats. Diabetes 37: 1695–1702
L'Esperance FA Jr, James WA, Judson PH (1990) The eye and diabetes mellitus. In: Rifkin H, Porte D Jr (eds) Diabetes mellitus: theory and practice. Elsevier, New York, pp 661–683
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Tamsma, J.T., van den Born, J., Bruijn, J.A. et al. Expression of glomerular extracellular matrix components in human diabetic nephropathy: decrease of heparan sulphate in the glomerular basement membrane. Diabetologia 37, 313–320 (1994). https://doi.org/10.1007/BF00398060
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DOI: https://doi.org/10.1007/BF00398060