Patophysiology of diabetic retinopathy

Czech version

Published in: Vnitř Lék 2013; 59(3): 173-176
Category: Reviews

Overview

Diabetic retinopathy (DR) is the affection of the retina in patients with diabetes mellitus (DM). The basic causative factor is prolonged hyperglycaemia. DR is microangiopathy, ie impairment of retinal capillaries. Pathophysiology of DR is very complex and there are involved in many factors. The first and most fundamental factor is the failure blood-retinal barrier (BRB). The major mechanism causing malfunction of BRB are advanced glycation end-products (AGE). In the failure of the inner BRB are involved losses of endothelial cells in capillaries, together with the losses of pericytes. A very important role in the failure of BRB plays too increased adhesivity of leukocytes. Further important role play also AGE and their receptor RAGE. They stimulate cascade of pathological processes damaging BRB. The second important factors in the pathophysiology of DR are vasoactive factors. The most important is vascular endothelial growth factor (VEGF), further than protein kinase C (PKC), histamine, angiotensin II, matrix metaloproteinases. The third important factor in the pathophysiology of DR is the vitreoretinal interface. There plays important role detachment of posterior vitreous, cortical vitreous, internal limiting membrane.

Key words:
diabetic retinopathy – pathophysiology – diabetes mellitus – hematoretinal Barrier – VEGF – vitreoretinal interface

Sources

1. Pinach S, Burt D, Berrone E et al. Retinal heat shock protein 25 in early experimental diabetes. Acta Diabetol 2011; published online http://link.springer.com/article/10.1007/s00592-011-0346-1.

2. Coral K, Angayarkanni N, Gomathy N et al. Homocysteine levels in the vitreous of proliferative diabetic retinopathy and rhegmatogenous retinal detachment: its modulating role on lysyl oxidase. Invest Ophthalmol Vis Sci 2009; 50: 3607–3612.

3. Chung SS, Chung SK. Aldose reductase in diabetic microvascular complications. Curr Drug Targets 2005; 6: 475–486.

4. Bandello F, Lattanzio R, Zucchiatti I et al. Pathophysiology and treatment of diabetic retinopathy. Acta Diabetol 2012; 50: 1–20.

5. Wong HC, Boulton M, McLeod D et al. Retinal pigment epithelial cells in culture produce retinal vascular mitogens. Arch Ophthalmol. 1988; 106: 1439–1443.

6. Gillies MC, Su T, Stayt J et al. Effect of high glucose on permeability of retinal capillary endothelium in vitro. Invest Ophthalmol Vis Sci 1997; 38: 635–642.

7. Grimes PA, Laties AM. Early morphological alteration of the pigment epithelium in streptozotocin-induced diabetes: increased surface area of the basal cell membrane. Exp Eye Res 1980; 30: 631–639.

8. Kristinsson JK, Gottfredsdottir MS, Stefansson E. Retinal vessel dilatation and elongation precedes diabetic macular oedema. Br J Ophthalmol 1997; 81: 274–278.

9. Dosso AA, Leuenberger PM, Rungger-Brandle E. Remodeling of retinal capillaries in the diabetic hypertensive rat. Invest Ophthalmol Vis Sci 1999; 40: 2405–2410.

10. Joussen AM, Murata T, Tsujikawa A et al. Leukocytemediated endothelial cell injury and death in the diabetic retina. Am J Pathol. 2001;158:147–52

11. Joussen AM, Poulaki V, Le ML, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. Faseb J 2004; 18: 1450–1452.

12. Kaji Y, Usui T, Ishida S et al. Inhibition of diabetic leukostasis and blood – retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products. Invest Ophthalmol Vis Sci 2007; 48: 858–865.

13. Barile GR, Pachydaki SI, Tari SR et al. The RAGE axis in early diabetic retinopathy. Invest Ophthalmol Vis Sci 2005; 46: 2916–2924.

14. Lu M, Kuroki M, Amano S et al. Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest 1998; 101: 1219–1224.

15. Antonetti D, Lieth E, Barber A et al. Molecular mechanisms of vascular permeability in diabetic retinopathy. Sem Ophthalmol 1999; 14: 240–248.

16. Bhagat N, Grigorian RA, Tutela A et al. Diabetic macular edema: Pathogenesis and treatment. Surv Ophthalmol 2009; 54: 1–32.

17. Aiello LP, Bursell SE, Clermont A et al. Vascular endothelial growth factor – induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta isoform selective inhibitor. Diabetes 1997; 46: 1473–1480.

18. Sone H, Kawakami Y, Okuda Y et al. Ocular vascular endothelial growth factor levels in diabetic rats are elevated before observable retinal proliferative changes. Diabetologia 1997; 40: 726–730.

19. Hammes HP, Lin J, Bretzel RG et al. Upregulation of the vascular endothelial growth factor receptor system in experimental background diabetic retinopathy of the rat. Diabetes 1998; 47: 401–406.

20. Murata T, Nakagawa K, Khalil A et al. The relation between expression of vascular endothelial growth factor and breakdown of the blood--retinal barrier in diabetic rat retinas. Lab Invest 1996; 74: 819–825.

21. Chakrabarti S, Sima AAF. Endothelin 1 and endothelin 3 like immunoreactivity in the eyes of diabetic and non-diabetic BB/W rats. Diabetes Res Clin Pract 1997; 37: 109–120.

22. Chakravathy U, Gardiner TA, Archer DB et al. The effect of endothelin 1 on the retinal microvascular pericyte. Microvasc Res 1992; 43: 241–254.

23. Carroll WJ, Hollis TM. Aortic histamine synthesis and aortic albumin accumulation in diabetes: activity-uptake relationships. Exp Mol Pathol 1985; 42: 344–352.

24. Chua CC, Hamdy RC, Chua BH. Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells. Biochem Biophys Acta 1998; 1401: 187–194.

25. Jin M, Kashiwagi K, Iizuka Y et al. Matrix metalloproteinases in human diabetic and nondiabetic vitreous. Retina 2001; 21: 28–31.

26. Das A, McGuire PG, Eriqat C et al. Human diabetic neovascular membranes contain high levels of urokinase and metalloproteinase enzymes. Invest Ophthalmol Vis Sci 1999; 40: 809–813.

27. Ogata N, Tombran-Tink J, Nishikawa M et al. Pigment epithelium-derived factor in the vitreous is low in diabetic retinopathy and high in rhegmatogenous retinal detachment. Am J Ophthalmol 2001; 132: 378–382.

28. Lindahl P, Johansson BR, Leveen P et al. Pericyte loss and microaneurysm formation in PDGF-B--deficient mice. Science 1997; 277: 242–245.

29. McNeil PL, Muthukrishnan L, Warder E et al. Growth factors are released by mechanically wounded endothelial cells. J Cell Biol 1989; 109: 811–822.

30. Sakamoto T. Cell biology of hyalocytes. Nippon Ganka Gakkai Zasshi 2003; 107): 866-882, discussion 883.

31. Harbour JW, Smiddy WE, Flynn HWJ et al. Vitrectomy for diabetic macular edema associated with a thickened and taut posterior hyaloid membrane. Am J Ophthalmol 1996; 121: 405–413.

32. Sebag J. Anatomy and pathology of the vitreo-retinal interface. Eye 1992; 6: 541–552.

33. Lopes de Faria JM, Jalkh AE, Trempe CL et al. Diabetic macular edema: risk factors and concomitants. Acta Ophthalmol Scand 1999; 77: 170–175.

34. Huang D, Swanson EA, Lin CP et al. Optical coherence tomography. Science 1991; 254: 1178–1181.

35. Jalkh AE, Takahashi M, Topilow HW et al. Prognostic value of vitreous findings in diabetic retinopathy. Archives of Ophthalmology 1982; 100: 432–434.

36. Sebag J. Aging of the vitreous. Eye 1987; 1: 254–262.

37. Jumper JM, Embabi SN, Toth CA et al. Electron immunocytochemical analysis of posterior hyaloid associated with diabetic macular edema. Retina 2000; 20: 63–68.

38. Kon CH, Occlestone NL, Charteris D. A prospective study of matrix metalloproteinases in proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci 1998; 39: 1524–1529.

39. Massin P, Erginay A, Haouchine BJ et al. Retinal thickness in healthy and diabetic subjects measured using optical coherence tomography mapping software. Eur J Ophthalmol 2002; 12: 102–108.

40. Aiello LP, Northrup JM, Keyt BA et al. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 1995; 113: 1538–1544.

41. Sebag J, Balazs EA. Pathogenesis of cystoid macular edema: an anatomic consideration of vitreoretinal adhesions. Surv Ophthalmol 1984; 28: (Suppl.): 493–498.

42. Amin RH, Frank RN, Kennedy A et al. Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 1997; 38: 36–47.

43. Yamamoto T, Akabane N, Takeuchi S. Vitrectomy for diabetic macular edema: The role of posterior vitreous detachment and epimacular membrane. Am J Ophthalmol 2001; 132: 369–377.