Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Sep 27;91(20):9436–9440. doi: 10.1073/pnas.91.20.9436

Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease.

C W Yang 1, H Vlassara 1, E P Peten 1, C J He 1, G E Striker 1, L J Striker 1
PMCID: PMC44827  PMID: 7937785

Abstract

Several lines of evidence suggest that the excessive accumulation of extracellular matrix in the glomeruli of diabetic kidneys may be due to reactive intermediates forming between glucose and matrix proteins called advanced glycation end products (AGEs). Normal mice received AGE-modified mouse serum albumin i.p. for 4 weeks, and glomerular extracellular matrix, growth factor mRNA levels, and morphology were examined. We found that AGE induced an increase in glomerular extracellular matrix alpha 1(IV) collagen, laminin B1, and transforming growth factor beta 1 mRNA levels, as measured by competitive PCR, as well as glomerular hypertrophy. The AGE response was specific because the coadministration of an AGE inhibitor, aminoguanidine, reduced all these changes. We conclude that AGEs affected expression of genes implicated in diabetic kidney disease and may play a major role in nephropathy.

Full text

PDF
9436

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alpers C. E., Hudkins K. L., Gown A. M., Johnson R. J. Enhanced expression of "muscle-specific" actin in glomerulonephritis. Kidney Int. 1992 May;41(5):1134–1142. doi: 10.1038/ki.1992.173. [DOI] [PubMed] [Google Scholar]
  2. Ayo S. H., Radnik R. A., Glass W. F., 2nd, Garoni J. A., Rampt E. R., Appling D. R., Kreisberg J. I. Increased extracellular matrix synthesis and mRNA in mesangial cells grown in high-glucose medium. Am J Physiol. 1991 Feb;260(2 Pt 2):F185–F191. doi: 10.1152/ajprenal.1991.260.2.F185. [DOI] [PubMed] [Google Scholar]
  3. Battegay E. J., Raines E. W., Seifert R. A., Bowen-Pope D. F., Ross R. TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell. 1990 Nov 2;63(3):515–524. doi: 10.1016/0092-8674(90)90448-n. [DOI] [PubMed] [Google Scholar]
  4. Bilous R. W., Mauer S. M., Sutherland D. E., Steffes M. W. Mean glomerular volume and rate of development of diabetic nephropathy. Diabetes. 1989 Sep;38(9):1142–1147. doi: 10.2337/diab.38.9.1142. [DOI] [PubMed] [Google Scholar]
  5. Brownlee M., Cerami A., Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988 May 19;318(20):1315–1321. doi: 10.1056/NEJM198805193182007. [DOI] [PubMed] [Google Scholar]
  6. Brownlee M., Vlassara H., Kooney A., Ulrich P., Cerami A. Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science. 1986 Jun 27;232(4758):1629–1632. doi: 10.1126/science.3487117. [DOI] [PubMed] [Google Scholar]
  7. Bruneval P., Foidart J. M., Nochy D., Camilleri J. P., Bariety J. Glomerular matrix proteins in nodular glomerulosclerosis in association with light chain deposition disease and diabetes mellitus. Hum Pathol. 1985 May;16(5):477–484. doi: 10.1016/s0046-8177(85)80086-1. [DOI] [PubMed] [Google Scholar]
  8. Cagliero E., Roth T., Roy S., Lorenzi M. Characteristics and mechanisms of high-glucose-induced overexpression of basement membrane components in cultured human endothelial cells. Diabetes. 1991 Jan;40(1):102–110. doi: 10.2337/diab.40.1.102. [DOI] [PubMed] [Google Scholar]
  9. Carome M. A., Striker L. J., Peten E. P., Moore J., Yang C. W., Stetler-Stevenson W. G., Striker G. E. Human glomeruli express TIMP-1 mRNA and TIMP-2 protein and mRNA. Am J Physiol. 1993 Jun;264(6 Pt 2):F923–F929. doi: 10.1152/ajprenal.1993.264.6.F923. [DOI] [PubMed] [Google Scholar]
  10. Doi T., Vlassara H., Kirstein M., Yamada Y., Striker G. E., Striker L. J. 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 U S A. 1992 Apr 1;89(7):2873–2877. doi: 10.1073/pnas.89.7.2873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Edelstein D., Brownlee M. Mechanistic studies of advanced glycosylation end product inhibition by aminoguanidine. Diabetes. 1992 Jan;41(1):26–29. doi: 10.2337/diab.41.1.26. [DOI] [PubMed] [Google Scholar]
  12. Floege J., Burns M. W., Alpers C. E., Yoshimura A., Pritzl P., Gordon K., Seifert R. A., Bowen-Pope D. F., Couser W. G., Johnson R. J. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int. 1992 Feb;41(2):297–309. doi: 10.1038/ki.1992.42. [DOI] [PubMed] [Google Scholar]
  13. Floege J., Eng E., Young B. A., Johnson R. J. Factors involved in the regulation of mesangial cell proliferation in vitro and in vivo. Kidney Int Suppl. 1993 Jan;39:S47–S54. [PubMed] [Google Scholar]
  14. Fukui M., Nakamura T., Ebihara I., Shirato I., Tomino Y., Koide H. ECM gene expression and its modulation by insulin in diabetic rats. Diabetes. 1992 Dec;41(12):1520–1527. doi: 10.2337/diab.41.12.1520. [DOI] [PubMed] [Google Scholar]
  15. Glick A. D., Jacobson H. R., Haralson M. A. Mesangial deposition of type I collagen in human glomerulosclerosis. Hum Pathol. 1992 Dec;23(12):1373–1379. doi: 10.1016/0046-8177(92)90057-a. [DOI] [PubMed] [Google Scholar]
  16. Jaffer F., Saunders C., Shultz P., Throckmorton D., Weinshell E., Abboud H. E. Regulation of mesangial cell growth by polypeptide mitogens. Inhibitory role of transforming growth factor beta. Am J Pathol. 1989 Aug;135(2):261–269. [PMC free article] [PubMed] [Google Scholar]
  17. Kirstein M., Aston C., Hintz R., Vlassara H. Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins. J Clin Invest. 1992 Aug;90(2):439–446. doi: 10.1172/JCI115879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kirstein M., Brett J., Radoff S., Ogawa S., Stern D., Vlassara H. Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging. Proc Natl Acad Sci U S A. 1990 Nov;87(22):9010–9014. doi: 10.1073/pnas.87.22.9010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. MacKay K., Striker L. J., Stauffer J. W., Agodoa L. Y., Striker G. E. Relationship of glomerular hypertrophy and sclerosis: studies in SV40 transgenic mice. Kidney Int. 1990 Feb;37(2):741–748. doi: 10.1038/ki.1990.41. [DOI] [PubMed] [Google Scholar]
  20. Makita Z., Radoff S., Rayfield E. J., Yang Z., Skolnik E., Delaney V., Friedman E. A., Cerami A., Vlassara H. Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med. 1991 Sep 19;325(12):836–842. doi: 10.1056/NEJM199109193251202. [DOI] [PubMed] [Google Scholar]
  21. Makita Z., Vlassara H., Cerami A., Bucala R. Immunochemical detection of advanced glycosylation end products in vivo. J Biol Chem. 1992 Mar 15;267(8):5133–5138. [PubMed] [Google Scholar]
  22. Miyata S., Monnier V. Immunohistochemical detection of advanced glycosylation end products in diabetic tissues using monoclonal antibody to pyrraline. J Clin Invest. 1992 Apr;89(4):1102–1112. doi: 10.1172/JCI115690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pesce C. M., Striker L. J., Peten E., Elliot S. J., Striker G. E. Glomerulosclerosis at both early and late stages is associated with increased cell turnover in mice transgenic for growth hormone. Lab Invest. 1991 Nov;65(5):601–605. [PubMed] [Google Scholar]
  24. Peten E. P., Garcia-Perez A., Terada Y., Woodrow D., Martin B. M., Striker G. E., Striker L. J. Age-related changes in alpha 1- and alpha 2-chain type IV collagen mRNAs in adult mouse glomeruli: competitive PCR. Am J Physiol. 1992 Nov;263(5 Pt 2):F951–F957. doi: 10.1152/ajprenal.1992.263.5.F951. [DOI] [PubMed] [Google Scholar]
  25. Peten E. P., Striker L. J., Carome M. A., Elliott S. J., Yang C. W., Striker G. E. The contribution of increased collagen synthesis to human glomerulosclerosis: a quantitative analysis of alpha 2IV collagen mRNA expression by competitive polymerase chain reaction. J Exp Med. 1992 Dec 1;176(6):1571–1576. doi: 10.1084/jem.176.6.1571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Peten E. P., Striker L. J., Garcia-Perez A., Striker G. E. Studies by competitive PCR of glomerulosclerosis in growth hormone transgenic mice. Kidney Int Suppl. 1993 Jan;39:S55–S58. [PubMed] [Google Scholar]
  27. Reichard P., Nilsson B. Y., Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993 Jul 29;329(5):304–309. doi: 10.1056/NEJM199307293290502. [DOI] [PubMed] [Google Scholar]
  28. Skolnik E. Y., Yang Z., Makita Z., Radoff S., Kirstein M., Vlassara H. Human and rat mesangial cell receptors for glucose-modified proteins: potential role in kidney tissue remodelling and diabetic nephropathy. J Exp Med. 1991 Oct 1;174(4):931–939. doi: 10.1084/jem.174.4.931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Soulis-Liparota T., Cooper M., Papazoglou D., Clarke B., Jerums G. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes. 1991 Oct;40(10):1328–1334. doi: 10.2337/diab.40.10.1328. [DOI] [PubMed] [Google Scholar]
  30. Vlassara H., Brownlee M., Manogue K. R., Dinarello C. A., Pasagian A. Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling. Science. 1988 Jun 10;240(4858):1546–1548. doi: 10.1126/science.3259727. [DOI] [PubMed] [Google Scholar]
  31. Vlassara H., Fuh H., Makita Z., Krungkrai S., Cerami A., Bucala R. Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: a model for diabetic and aging complications. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12043–12047. doi: 10.1073/pnas.89.24.12043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Vlassara H. Receptor-mediated interactions of advanced glycosylation end products with cellular components within diabetic tissues. Diabetes. 1992 Oct;41 (Suppl 2):52–56. doi: 10.2337/diab.41.2.s52. [DOI] [PubMed] [Google Scholar]
  33. Yamamoto T., Nakamura T., Noble N. A., Ruoslahti E., Border W. A. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1814–1818. doi: 10.1073/pnas.90.5.1814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Yang C. W., Striker L. J., Pesce C., Chen W. Y., Peten E. P., Elliot S., Doi T., Kopchick J. J., Striker G. E. Glomerulosclerosis and body growth are mediated by different portions of bovine growth hormone. Studies in transgenic mice. Lab Invest. 1993 Jan;68(1):62–70. [PubMed] [Google Scholar]
  35. Ziyadeh F. N. The extracellular matrix in diabetic nephropathy. Am J Kidney Dis. 1993 Nov;22(5):736–744. doi: 10.1016/s0272-6386(12)80440-9. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES