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. 1996 Jan 1;97(1):238–243. doi: 10.1172/JCI118397

Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats.

J L Wautier 1, C Zoukourian 1, O Chappey 1, M P Wautier 1, P J Guillausseau 1, R Cao 1, O Hori 1, D Stern 1, A M Schmidt 1
PMCID: PMC507085  PMID: 8550841

Abstract

Dysfunctional endothelium is associated with and, likely, predates clinical complications of diabetes mellitus, by promoting increased vascular permeability and thrombogenicity. Irreversible advanced glycation end products (AGEs), resulting from nonenzymatic glycation and oxidation of proteins or lipids, are found in plasma, vessel wall, and tissues and have been linked to the development of diabetic complications. The principal means through which AGEs exert their cellular effects is via specific cellular receptors, one of which, receptor for AGE (RAGE), is expressed by endothelium. We report that blockade of RAGE inhibits AGE-induced impairment of endothelial barrier function, and reverse, in large part, the early vascular hyperpermeability observed in diabetic rats. Inhibition of AGE- and diabetes-mediated hyperpermeability by antioxidants, both in vitro and in vivo, suggested the central role of AGE-RAGE-induced oxidant stress in the development of hyperpermeability. Taken together, these data support the concept that ligation of AGEs by endothelial RAGE induces cellular dysfunction, at least in part by an oxidant-sensitive mechanism, contributing to vascular hyperpermeability in diabetes, and that RAGE is central to this pathologic process.

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Selected References

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  1. Albelda S. M., Sampson P. M., Haselton F. R., McNiff J. M., Mueller S. N., Williams S. K., Fishman A. P., Levine E. M. Permeability characteristics of cultured endothelial cell monolayers. J Appl Physiol (1985) 1988 Jan;64(1):308–322. doi: 10.1152/jappl.1988.64.1.308. [DOI] [PubMed] [Google Scholar]
  2. Baynes J. W. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991 Apr;40(4):405–412. doi: 10.2337/diab.40.4.405. [DOI] [PubMed] [Google Scholar]
  3. Brett J., Schmidt A. M., Yan S. D., Zou Y. S., Weidman E., Pinsky D., Nowygrod R., Neeper M., Przysiecki C., Shaw A. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol. 1993 Dec;143(6):1699–1712. [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. David G. S., Reisfeld R. A. Protein iodination with solid state lactoperoxidase. Biochemistry. 1974 Feb 26;13(5):1014–1021. doi: 10.1021/bi00702a028. [DOI] [PubMed] [Google Scholar]
  6. Esposito C., Gerlach H., Brett J., Stern D., Vlassara H. Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties. J Exp Med. 1989 Oct 1;170(4):1387–1407. doi: 10.1084/jem.170.4.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Mattock M. B., Morrish N. J., Viberti G., Keen H., Fitzgerald A. P., Jackson G. Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes. 1992 Jun;41(6):736–741. doi: 10.2337/diab.41.6.736. [DOI] [PubMed] [Google Scholar]
  8. Parving H. H., Viberti G. C., Keen H., Christiansen J. S., Lassen N. A. Hemodynamic factors in the genesis of diabetic microangiopathy. Metabolism. 1983 Sep;32(9):943–949. doi: 10.1016/0026-0495(83)90210-x. [DOI] [PubMed] [Google Scholar]
  9. Ritthaler U., Deng Y., Zhang Y., Greten J., Abel M., Sido B., Allenberg J., Otto G., Roth H., Bierhaus A. Expression of receptors for advanced glycation end products in peripheral occlusive vascular disease. Am J Pathol. 1995 Mar;146(3):688–694. [PMC free article] [PubMed] [Google Scholar]
  10. Ruderman N. B., Williamson J. R., Brownlee M. Glucose and diabetic vascular disease. FASEB J. 1992 Aug;6(11):2905–2914. doi: 10.1096/fasebj.6.11.1644256. [DOI] [PubMed] [Google Scholar]
  11. Schmidt A. M., Hasu M., Popov D., Zhang J. H., Chen J., Yan S. D., Brett J., Cao R., Kuwabara K., Costache G. Receptor for advanced glycation end products (AGEs) has a central role in vessel wall interactions and gene activation in response to circulating AGE proteins. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8807–8811. doi: 10.1073/pnas.91.19.8807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Schmidt A. M., Hori O., Brett J., Yan S. D., Wautier J. L., Stern D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb. 1994 Oct;14(10):1521–1528. doi: 10.1161/01.atv.14.10.1521. [DOI] [PubMed] [Google Scholar]
  13. Schmidt A. M., Vianna M., Gerlach M., Brett J., Ryan J., Kao J., Esposito C., Hegarty H., Hurley W., Clauss M. Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. J Biol Chem. 1992 Jul 25;267(21):14987–14997. [PubMed] [Google Scholar]
  14. Schmidt A. M., Yan S. D., Brett J., Mora R., Nowygrod R., Stern D. Regulation of human mononuclear phagocyte migration by cell surface-binding proteins for advanced glycation end products. J Clin Invest. 1993 May;91(5):2155–2168. doi: 10.1172/JCI116442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Shasby D. M., Roberts R. L. Transendothelial transfer of macromolecules in vitro. Fed Proc. 1987 Jun;46(8):2506–2510. [PubMed] [Google Scholar]
  16. Viberti G. C. Increased capillary permeability in diabetes mellitus and its relationship to microvascular angiopathy. Am J Med. 1983 Nov 30;75(5B):81–84. doi: 10.1016/0002-9343(83)90257-7. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Wautier J. L., Paton R. C., Wautier M. P., Pintigny D., Abadie E., Passa P., Caen J. P. Increased adhesion of erythrocytes to endothelial cells in diabetes mellitus and its relation to vascular complications. N Engl J Med. 1981 Jul 30;305(5):237–242. doi: 10.1056/NEJM198107303050501. [DOI] [PubMed] [Google Scholar]
  19. Wautier J. L., Wautier M. P., Schmidt A. M., Anderson G. M., Hori O., Zoukourian C., Capron L., Chappey O., Yan S. D., Brett J. Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7742–7746. doi: 10.1073/pnas.91.16.7742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Williamson J. R., Chang K., Tilton R. G., Prater C., Jeffrey J. R., Weigel C., Sherman W. R., Eades D. M., Kilo C. Increased vascular permeability in spontaneously diabetic BB/W rats and in rats with mild versus severe streptozocin-induced diabetes. Prevention by aldose reductase inhibitors and castration. Diabetes. 1987 Jul;36(7):813–821. doi: 10.2337/diab.36.7.813. [DOI] [PubMed] [Google Scholar]
  21. Yamaoka K., Nakagawa T., Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm. 1978 Apr;6(2):165–175. doi: 10.1007/BF01117450. [DOI] [PubMed] [Google Scholar]
  22. Yan S. D., Schmidt A. M., Anderson G. M., Zhang J., Brett J., Zou Y. S., Pinsky D., Stern D. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem. 1994 Apr 1;269(13):9889–9897. [PubMed] [Google Scholar]
  23. Yang Z., Makita Z., Horii Y., Brunelle S., Cerami A., Sehajpal P., Suthanthiran M., Vlassara H. Two novel rat liver membrane proteins that bind advanced glycosylation endproducts: relationship to macrophage receptor for glucose-modified proteins. J Exp Med. 1991 Sep 1;174(3):515–524. doi: 10.1084/jem.174.3.515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Yaqoob M., Patrick A. W., McClelland P., Stevenson A., Mason H., White M. C., Bell G. M. Relationship between markers of endothelial dysfunction, oxidant injury and tubular damage in patients with insulin-dependent diabetes mellitus. Clin Sci (Lond) 1993 Nov;85(5):557–562. doi: 10.1042/cs0850557. [DOI] [PubMed] [Google Scholar]
  25. Zatz R., Dunn B. R., Meyer T. W., Anderson S., Rennke H. G., Brenner B. M. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest. 1986 Jun;77(6):1925–1930. doi: 10.1172/JCI112521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. el Khoury J., Thomas C. A., Loike J. D., Hickman S. E., Cao L., Silverstein S. C. Macrophages adhere to glucose-modified basement membrane collagen IV via their scavenger receptors. J Biol Chem. 1994 Apr 8;269(14):10197–10200. [PubMed] [Google Scholar]

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