Basement Membranes in Disease

Kidney International (1993) 43, 114–120; doi:10.1038/ki.1993.19

Renal tubular basement membrane and collagen type IV in diabetes mellitus

Fuad N Ziyadeh1

1Renal-Electrolyte Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence: Fuad N Ziyadeh MD, Renal-Electrolyte Division, 700 Clinical Research Building, University of Pennsylvania, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6144, USA.

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Abstract

Renal tubular basement membrane and collagen type IV in diabetes mellitus. The pathogenesis of the multiple structural lesions in diabetic nephropathy remains debated, and likely is multifactorial. The uniform thickening of the renal basement membranes lining the glomerular and tubular elements appears to be a consequence of the metabolic perturbations which are directly related to hyperglycemia. While most investigations have focused on the increased accumulation of extracellular matrix in the glomerular basement membrane and the mesangium, and their relation to derangements in glomerular function, little is known regarding the pathogenesis and the significance Of the tubulointerstitial changes and the thickened tubular basement membrane (TBM). It is possible that these latter changes are causally related to the cellular hypertrophy of the renal tubular epithelium that lines the TBM. It has been postulated that in the earlier stages of the disease, hyperglycemia induces renal tubular hypertrophy and stimulates the synthesis of the various matrix components which are normal constituents of the TBM. Later, the structural composition of the TBM is susceptible to further modifications by non-enzymatic glycation, and this aberrant process may impart a relative resistance to matrix degradation leading to a slow turnover. In vitro investigations on murine proximal tubule cells in culture have provided evidence that elevated ambient glucose is a sufficient stimulus for cellular hypertrophy and increased biosynthesis of collagen type IV, the predominant constituent of TBM. High glucose levels increase steady-state collagen IV mRNA, partly due to transcriptional activation of cis-acting elements of the gene which are controlled by putative glucose-responsive trans-acting proteins. This effect of hyperglycemia may be the consequence of increased activity of the polyol pathway, with attendant alterations in cellular myo-inositol metabolism. Treatment with sorbinil, an aldose reductase inhibitor, or supplementation of the medium with supra-physiologic levels of myo-inositol, prevents the stimulation by high glucose of the increased secretion and biosynthesis of collagen IV. The glucose-induced cellular hypertrophy, however, is minimally aifected by these maneuvers, and may result from activation of humoral or local mediators including transforming growth factor-beta.

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References

  1. Ziyadeh FN, Goldfarb S: The renal tubulointerstitium in diabetes mellitus. Kidney Int 39:464–475, 1991 | PubMed | ISI | ChemPort |
  2. Mauer SM, Steffes MW, Ellis EN, Sutherland DER, Brown DM, Goetz FC: Structural-functional relationships in diabetic nephropathy. J Clin Invest 74:1143–1155, 1984 | PubMed | ISI | ChemPort |
  3. Bohle A, Bader R, Grund KE, MacKensen S, Tolon M: Correlations between renal interstitium and level of serum creatinine. Morphometric investigations of biopsies in perimembranous glomerulonephritis. Virchows Arch A Path Anat Histol 373:15–22, 1977
  4. Deckert T, Parving HH, Thomsen OF, Jorgensen HE, Brun C, Thomsen AC: Renal structure and function in type I (insulin-dependent) diabetic patients. Diabetic Neph 4:163–168, 1986
  5. Horlyck A, Gunderson HJG, Osterby R: The cortical distribution pattern of diabetic glomerulopathy. Diabetologia 29:146–150, 1986
  6. Kleinman KS, Fine LG: Prognostic implications of renal hypertrophy in diabetes mellitus. Diab Metab Rev 4:179–189, 1988
  7. Seyer-Hansen K, Hansen J, Gunderson HJG: Renal hypertrophy in experimental diabetes. A morphometric study. Diabetologia 18:501–505, 1980 | PubMed | ChemPort |
  8. Rasch R: Tubular lesions in streptozotocin diabetic rats. Diabetologia 27:32–37, 1984 | PubMed | ISI | ChemPort |
  9. Fogo A, Ichikawa I: Evidence for the central role of glomerular growth promoters in the development of sclerosis. Sem Nephrol 9:329–342, 1989
  10. Osterby R, Gundersen HJG: Fast accumulation of basement membrane material and the rate of morphological changes in acute experimental diabetic glomerular hypertrophy. Diabetologia 18:493–500, 1980 | PubMed | ISI | ChemPort |
  11. Cohen MP, Surma M: Renal glomerular basement membrane. In vivo biosynthesis and turnover in normal rats. J Biol Chem 225:1767–1770, 1980
  12. Ziyadeh FN, Snipes ER, Watanabe M, Alvarez RJ, Goldfarb S, Haverty TP: High glucose induces cell hypertrophy and stimulates collagen gene transcription in proximal tubule. Am J Physiol 259(Renal Fluid Electrol Physiol 28):F704–F714, 1990 | PubMed | ISI | ChemPort |
  13. Adler S, Anderson P, Xu G, Ihm C, Nast C, Gullermo R, Glassock R: Early renal procollagen alpha1 (IV) gene expression in diabetic rats occurs deep to superficial cortical glomeruli. (abstract) Clin Res 37:484A, 1989
  14. Lee GCL, Nast CC, Ihm CG, Guillermo R, Levin PS, Glassock RJ, Adler SG: Renal hypertrophy preceded elevated procollagen alpha1 (IV) mRNA levels after 1-22/33 nephrectomy. (abstract) J Am Soc Nephrol 1:635, 1990
  15. Wolf G, Killen PD, Neilson EG: Intracellular signaling of transcription and secretion of type IV collagen after angiotensin II-induced cellular hypertrophy in cultured proximal tubular cells. Cell Reg 2:219–227, 1991
  16. Wolf G, Neilson EG, Goldfarb S, Ziyadeh FN: The influence of glucose concentration on angiotensin II-induced hypertrophy of proximal tubular cells in culture. Biochem Biophys Res Commun 176:902–909, 1991 | Article | PubMed | ISI | ChemPort |
  17. Osterby R: Early phases in the development of diabetic glomerulopathy. A quantitative electron microscopic study. Acta Med Scand 574(Suppl):1–82, 1975
  18. Mauer SM, Ellis EN, Bilous RW, Steffes MW: The pathology of diabetic nephropathy, in Complications of Diabetes Mellitus, edited by B Drazin, S Melmed, D LeRoith, New York, Alan R. Liss, 1989, pp. 95–101
  19. Steffes MW, Barbosa J, Basgen JM, Sutherland DER, Najarian JS, Mauer SM: Quantitative glomerular morphology of the normal human kidney. Lab Invest 49:82–86, 1983 | PubMed | ISI | ChemPort |
  20. Steffes MW, Sutherland DER, Goetz FC, Rich SS, Mauer SM: Studies of kidney and muscle biopsy specimens from identical twins discordant for type I diabetes mellitus. N Engl J Med 312:1282–1287, 1985
  21. Michael AF, Brown DM: Increased concentration of albumin in kidney basement membranes in diabetes mellitus. Diabetes 30:843–846, 1981
  22. Murrah V, Crosson J, Sauk J: Abnormal binding of negatively charged serum proteins to diabetic basement membranes is largely a systemic phenomenon. Virchows Arch 405:141–154, 1984
  23. Sato T, Munakata H, Yoshinaga K, Yosizawa Z: Comparison of the chemical composition of glomerular and tubular basement membranes obtained from human kidneys of diabetics and non-diabetics. Clin Chim Acta 61:145–159, 1975
  24. Wahl P, Deppermann D, Hasslacher H: Biochemistry of glomerular basement membrane of the normal and diabetic human. Kidney Int 21:744–749, 1982 | ChemPort |
  25. Brownlee M, Cerami A: The biochemistry of complications of diabetes mellitus. Ann Rev Biochem 50:385–432, 1981
  26. Sternberg M, Cohen-Fortere L, Peyroux J: Connective tissue in diabetes mellitus: Biochemical alterations of the extra-cellular matrix with special reference to proteoglycans, collagens and basement membranes. Diab et Metab 11:27–50, 1985
  27. Ziyadeh FN, Goldfarb S, Kern EFO: Diabetic nephropathy: Metabolic and biochemical mechanisms, in Contemporary Issues in Nephrology 20. The Kidney in Diabetes Mellitus, edited by BM Brenner, JH Stein, New York, Churchill Livingston, 1989, pp. 87–113
  28. Cohen-Forterre L, Mozere G, Andre J, Sternberg M: Studies on kidney sialidase in normal and diabetic rats. Biochim Biophys Acta 801:138–145, 1984
  29. Falk RJ, Scheinman JI, Mauer SM, Michael AF: Poly-antigenic expansion of basement membrane constituents in diabetic nephropathy. Diabetes 32(Suppl 2):34–39, 1983 | PubMed | ISI |
  30. Desjardins M, Gros F, Wieslander J, Gubler MC, Bendayan M: Immunogold studies of monomeric elements from the globular domain (NC1) of type IV collagen in renal basement membranes during experimental diabetes in the rat. Diabetologia 33:661–670, 1990
  31. Hostikka SL, Eddy RL, Byers MG, Hoyhtya M, Shows TB, Tryggvason K: Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc Natl Acad Sci USA 87:1606–1610, 1990 | PubMed | ChemPort |
  32. Brownlee M: Glycosylation products as toxic mediators of diabetic complications. Ann Rev Med 42:159–166, 1991
  33. Trueb B, Fluckiger R, Winterhalter KH: Non-enzymatic glycosylation of basement membrane collagen in diabetes mellitus. Coll Rel Res 4:239–251, 1984
  34. Yano M, Mizuno A, Shima K: Immunohistochemical localization of glycated protein in diabetic rat kidney. Diabetes Res Clin Pract 8:215–219, 1990
  35. Brownlee M, Cerami A, Vlassara H: Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318:1315–1321, 1988 | PubMed | ISI | ChemPort |
  36. Cohen MP: Nonenzymatic glycation and enhanced polyol pathway activity in the pathogenesis of diabetic nephropathy, in Diabetes and the Kidney, edited by A Heidland, KM Koch, E Heidbreder Contrib Nephrol, Basel, Karger, 1989, pp. 59–72
  37. Belfiore F, Iannello S, Rabuazzo AM, Campione R: Increased hexokinase/glucose-6-phosphatase ratio in the diabetic kidney as index of glucose overutilization. Clin Physiol Biochem 7:223–228, 1989
  38. Cortes P, Levin NW, Dumler F, Rubenstein AH, Verghese CP, Venkatachalam KK: Uridine triphosphate and RNA synthesis during diabetes-induced renal growth. Am J Physiol 238:E349–E357, 1980
  39. Schwieger J, Fine LG: Renal hypertrophy, growth factors, and nephropathy in diabetes mellitus. Semin Nephrol 10:242–253, 1990 | PubMed | ISI | ChemPort |
  40. Poulsom R, Kurkinen M, Prockop DJ, Boot-Hanford RP: Increased steady-state levels of laminin B1 mRNA in kidneys of long-term streptozotocin-diabetic rats. No effect of aldose reductase inhibitor. J Biol Chem 263:10072–10076, 1988 | PubMed | ISI | ChemPort |
  41. Ledbetter S, Copeland EJ, Noonan D, Vogeli G, Hassell JR: Altered steady state mRNA levels of basement membrane proteins in diabetic mouse kidneys and thromboxane synthase inhibition. Diabetes 39:196–203, 1990 | PubMed | ISI | ChemPort |
  42. Killen PD, Ebihara I, Martin GR, Ortola F, Brenner BM: mRNA levels for laminin and collagen IV chains are elevated in diabetic kidneys. (abstract) Kidney Int 31:171, 1987
  43. Roy S, Sala R, Cagliero E, Lorenzi M: Overexpression of fibronectin induced by diabetes or high glucose: Phenomenon with a memory. Proc Natl Acad Sci USA 87:404–408, 1990 | PubMed | ChemPort |
  44. Ayo SH, Radnik RA, Glass WF, Garoni JA, Rampt ER, Appling DR, Kreisberg JI: Increased extracellular matrix synthesis and mRNA in mesangial cells grown in high-glucose medium. Am J Physiol 260:F185–F191, 1991 | PubMed | ISI | ChemPort |
  45. Hasslacher CH, Wahl P: Influence of diabetes control on synthesis of protein and basement membrane collagen in isolated glomeruli of diabetic rats. Res Exp Med 176:247–253, 1980
  46. Risteli J, Koivisto VA, Akerblom HK, Kivirikko KI: Intracellular enzymes of collagen biosynthesis in rat kidney in streptozotocin diabetes. Diabetes 25:1066–1070, 1976
  47. Hasslacher C, Reichenbacher R, Gechter F, Timpl R: Glomerular basement membrane synthesis and serum concentration of type IV collagen in streptozotocin-diabetic rats. Diabetologia 26:150–157, 1984
  48. Matsumoto E, Matsumoto G, Ooshima A, Kikuoka H, Bessho H, Miyamura K, Nanjo K: Serum type IV collagen concentrations in diabetic patients with microangiopathy as determined by enzyme immunoassay with monoclonal antibodies. Diabetes 39:885–890, 1990
  49. Price RG, Spiro RG: Studies on the metabolism of the renal glomerular basement membrane. Turnover measurements in the rat with the use of radiolabeled amino acids. J Biol Chem 252:8597–8602, 1977 | PubMed | ISI | ChemPort |
  50. Romen W, Lange HW, Hempel R, Heck T: Studies on collagen metabolism in rats. II. Turnover and amino acid composition of the collagen of glomerular basement membrane in diabetes mellitus. Virchows Arch 36:313–320, 1981
  51. Cohen MP, Surma ML, Wu VY: In vivo biosynthesis and turnover of glomerular basement membrane in diabetic rats. Am J Physiol 242:F385–F389, 1982
  52. Lubec G, Leban J, Peyroux J, Sternberg M, Pollack A, Latzka M, Coradello H: Reduced collagenolytic activity of rat kidneys with streptozotocin diabetes. Nephron 30:357–360, 1982
  53. Monnier VM, Kohn RR, Cerami A: Accelerated age-related browning of collagen in diabetes mellitus. Proc Natl Acad Sci USA 81:583–587, 1984 | Article | PubMed | ChemPort |
  54. Nicholls K, Mandel TE: Advanced glycosylation end-products in experimental murine diabetic nephropathy: Effect of islet isografting and of aminoguanidine. Lab Invest 60:486–491, 1989
  55. Lubec G, Pollak A: Reduced susceptibility of nonenzymatically glucosyiated glomerular basement membrane to proteases. Renal Physiol 3:4–8, 1980
  56. Greene DA, DeJesus PV Jr, Winegrad AI: Effects of insulin and dietary myoinositol on impaired motor nerve conduction velocity in acute streptozotocin diabetes. J Clin Invest 55:1326–1336, 1975
  57. Greene DA, Lattimer SA, Sima AAF: Sorbitol, phosphoinositides and the sodium-potassium ATPase in the pathogenesis of diabetic complications. N Engl J Med 316:599–606, 1987 | PubMed | ISI | ChemPort |
  58. Simmons DA, Winegrad AI: Mechanism of glucose-induced (Na+, K+)-ATPase inhibition in aortic wall of rabbits. Diabetologia 32:402–408, 1989
  59. Goldfarb S, Ziyadeh FN, Kern EFO, Simmons D: Effects of polyol pathway inhibition and dietary myo-inositol on glomerular hemodynamic function in experimental diabetes mellitus in the rat. Diabetes 40:465–471, 1991 | PubMed |
  60. Pedersen MM, Christiansen JS, Mogensen CE: Reduction of glomerular hyperfiltration in normoalbuminuric IDDM patients by 6 months of aldose reductase inhibition. Diabetes 40:527–531, 1991 | PubMed | ISI | ChemPort |
  61. Cohen MP, Klepser H, Wu VY: Heparan sulfate of glomerular basement membrane is undersulfated in experimental diabetes and is not corrected with aldose reductase inhibition. Diabetes 37:1324–1327, 1988 | PubMed | ISI | ChemPort |
  62. Mauer SM, Steffes MW, Azar S, Brown DM: Effects of sorbinil on glomerular structure and function in long-term diabetic rats. Diabetes 38:839–846, 1989
  63. Beyer-Mears A, Ku L, Cohen MP: Glomerular polyol accumulation in diabetes and its prevention by oral sorbinil. Diabetes 33:604–607, 1984 | PubMed | ChemPort |
  64. Snipes ER, Watanabe M, Simmons DA, Goldfarb S, Ziyadeh FN: Polyol pathway activation in high-glucose stimulation of procollagen transcription and secretion in proximal tubule cells. (abstract) J Am Soc Nephrol 1:642, 1990
  65. Ziyadeh FN, Simmons DA, Snipes ER, Goldfarb S, Haverty TP: Effect of myo-inositol on cell proliferation and collagen transcription and secretion in proximal tubule cells cultured in elevated glucose. J Am Soc Nephrol 1:1220–1229, 1991 | PubMed | ChemPort |
  66. Suarez G, Rajaram R, Bhuyan KC, Oronsky AL, Goidl JA: Administration of an aldose reductase inhibitor induces a decrease of collagen fluorescence in diabetic rats. J Clin Invest 82:624–627, 1988
  67. Szwergold BS, Kappler F, Brown TR: Identification of fructose 3-phosphate in the lens of diabetic rats. Science 247:451–454, 1990
  68. Petersen A, Szwergold BS, Kappler F, Weingarten M, Brown TR: Identification of sorbitol 3-phosphate and fructose 3-phosphate in normal and diabetic human erythrocytes. J Biol Chem 265:17424–17427, 1990 | PubMed | ChemPort |
  69. Blazer-Yost BL, Goldfarb S, Ziyadeh FN: Insulin, insulin-like growth factors and the kidney, in Contemporary Issues in Nephrology 23. Hormones, Autacoids and the Kidney, edited by S Goldfarb, FN Ziyadeh, New York, Churchill Livingstone, 1991, pp. 339–363
  70. Rocco MV, Ziyadeh FN: Transforming growth factor-beta: An update on systemic and renal actions, in Contemporary Issues in Nephrology 23. Hormones, Autacoids and the Kidney, edited by S Goldfarb, FN Ziyadeh, New York, Churchill Livingstone, 1991, pp. 391–410
  71. Rocco MV, Chen Y, Goldfarb S, Ziyadeh FN: Elevated glucose levels stimulate transforming growth factor-beta gene expression and bioactivity in murine proximal tubule cell culture. Kidney Int 41:107–114, 1992 | PubMed | ISI | ChemPort |

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