PPARs in Eye Biology and DiseaseView this Special Issue
Review Article | Open Access
Yasuo Yanagi, "Role of Peoxisome Proliferator Activator Receptor on Blood Retinal Barrier Breakdown", PPAR Research, vol. 2008, Article ID 679237, 4 pages, 2008. https://doi.org/10.1155/2008/679237
Role of Peoxisome Proliferator Activator Receptor on Blood Retinal Barrier Breakdown
The retinal vessels have two barriers: the retinal pigment epithelium and the retinal vascular endothelium. Each barrier exhibits increased permeability under various pathological conditions. This condition is referred to as blood retinal barrier (BRB) breakdown. Clinically, the most frequently encountered condition causing BRB breakdown is diabetic retinopathy. In recent studies, inflammation has been linked to BRB breakdown and vascular leakage in diabetic retinopathy. Biological support for the role of inflammation in early diabetes is the adhesion of leukocytes to the retinal vasculature (leukostasis) observed in diabetic retinopathy. is a member of a ligand-activated nuclear receptor superfamily and plays a critical role in a variety of biological processes, including adipogenesis, glucose metabolism, angiogenesis, and inflammation. There is now strong experimental evidence to support the theory that inhibits diabetes-induced retinal leukostasis and leakage, playing an important role in the pathogenesis of diabetic retinopathy. Therapeutic targeting of may be beneficial to diabetic retinopathy.
1. Blood Retinal Barrier (BRB) Breakdown in Diabetic Retinopathy
The retinal vessels have a barrier consisting of the tight junction of the retinal pigment epithelium and the retinal vascular endothelium. Each barrier exhibits increased permeability under various pathological conditions. This condition is referred to as blood retinal barrier (BRB) breakdown. Clinically, the most frequently encountered condition that induces vascular permeability is diabetic retinopathy . BRB breakdown causes retinal edema. Clinically, the retinal edema often affects macula, the highly sensitive area of the central retina, and often severely affects vision (Figure 1). The frequency of diabetic macular edema ranges from 2% to 13.3% of all diabetic patients, and 6.7% to 62% of insulin-dependent diabetic patients, and its incidence is 1.3% to 5.1% over a four-year observation period . Due to the enhanced retinal vascular permeability, endothelial cell damage and capillary nonperfusion are aggravated. Much effort has been directed toward establishing effective treatments, and recent clinical studies have found that laser photocoagulation, pars plana vitrectomy, and antivascular endothelial growth factor (VEGF) therapy might be effective in ameliorating macular edema [3–6], but the treatment efficacy is limited and the results of the preliminary clinical investigation will have to be confirmed by further studies.
2. The Role of Inflammation in BRB Breakdown
In recent studies, inflammation has been linked to vascular leakage in diabetic retinopathy . Biological support for the role of inflammation in early diabetes is the adhesion of leukocytes to the retinal vasculature (leukostasis) observed in both experimental diabetic retinopathy in rats and in human diabetic retinopathy [8, 9]. Increased adhesion of leukocytes to the retinal vasculature is considered to promote vascular leakage. Thus, leukostasis is considered to be a critical event in the pathogenesis of diabetic retinopathy. Clinical investigations have demonstrated that the vitreous level of VEGF protein is higher in patients with diabetic macular edema than in patients with other conditions . Ample evidence suggests that the adhesion of leukocytes to the retinal capillaries is controlled by vascular endothelial growth factor (VEGF), and focal adhesion molecules such as the intercellular adhesion molecule 1 (ICAM1) . It is a commonly accepted molecular mechanism of leukocyte adhesion that VEGF drives the upregulation of the ICAM-1 molecule in the retinal endothelial cells [12, 13], and that this upregulated ICAM-1, together with upregulated leukocyte integrin CD18, triggers adhesion of leukocytes to the retinal vessels . Indeed, CD18(−/−) and ICAM-1 (−/−) mice demonstrate significantly fewer adherent leukocytes in the retinal vasculature after the induction of diabetes with streptozotocin (STZ) . It is, however, not only VEGF but also several other molecules that are involved in the expression of ICAM-1. NF-κB molecules, activated by inflammation, also drive ICAM-1 expression . Furthermore, blockage of the bioactivity of VEGF or ICAM-1 or inhibition of inflammatory pathways leads to decreased retinal leukocyte adhesion and reduced vascular leakage . Thus, it is generally assumed that the upregulation of the adhesion molecule, triggered by VEGF and other inflammatory stimuli, is important in the leukostasis (Figure 2).
3. PPARγ and Inflammation
PPARγ is a member of a ligand-activated nuclear receptor superfamily and plays a critical role in a variety of biological processes, including adipogenesis, glucose metabolism, angiogenesis, and inflammation . Synthetic ligands of PPARγ, that is, thiazolidine derivatives such as rosiglitazone and pioglitazone, are used as oral antihyperglycemic agents for the therapy of non-insulin-dependent diabetes mellitus. In addition, recent studies have shown that PPARγ ligands modulate the production of inflammatory mediators . Actually, it has been reported that PPARγ ligands, such as rosiglitazone and pioglitazone, suppress inflammatory diseases such as adjuvant-induced arthritis . Importantly, some evidence suggests that PPARγ is involved in the regulation of adhesion molecules. Previously, it has been demonstrated that PPARγ ligand suppressed ICAM-1 expression in a murine model of intestinal ischemia-reperfusion injury  and in human umbilical vein endothelial cells in vitro . Some of these anti-inflammatory functions are mediated through the inhibition of NF-κB activation (Figure 3). Considering the close link between inflammation and diabetes, it is rational to consider that PPARγ ligand therapy may also improve diabetic retinopathy.
4. PPARγ in BRB Breakdown
We investigated the effects of a synthetic PPARγ ligand, rosiglitazone, on an experimental diabetic model . Additionally, heterozygous PPARγ-deficient (+/-) mice were used in an experimental model to determine whether endogenous PPARγ played a role . Experimental diabetes was induced by intraperitoneal injection of STZ. This model is considered to destroy pancreatic beta cells completely  Retinal leukostasis quantification was performed by counting the number of adherent leukocytes after fluorescein-isothiocyanide (FITC)- Concanavalin A lectin (Con A) perfusion. A retinal leakage assay was performed by evaluating the retinal concentration of FITC-dextran after the animals were perfused. The results showed the PPARγ agonist, rosiglitazone, inhibited both the retinal leukostasis and retinal leakage observed in the experimental diabetic rats and that the decreased expression of the endogenous PPARγ in mice leads to the aggravation of retinal leukostasis and retinal leakage in diabetic mice. Together, these findings support the theory that the PPARγ signaling pathway inhibits diabetes-induced retinal leukostasis and leakage. In addition, it was demonstrated that PPARγ ligand suppresses ICAM-1 expression, but not VEGF expression, raising the possibility that NF-κB mediated ICAM-1 is suppressed by PPARγ ligand (Figure 4).
These results provide strong evidence to support the theory that PPARγ activity plays an important role in the pathogenesis of diabetic retinopathy and introduce the novel possibility that the therapeutic targeting of PPARγ may be beneficial to diabetic retinopathy.
- S. E. Moss, R. Klein, and B. E. Klein, “The 14-year incidence of visual loss in a diabetic population,” Ophthalmology, vol. 105, no. 6, pp. 998–1003, 1998.
- J.-F. Angers and A. Biswas, “A Bayesian analysis of the 4-year follow-up data of the Wilconsin epidemiologic study of diabetic retinopathy,” Statistics in Medicine, vol. 23, no. 4, pp. 601–615, 2004.
- G. M. Comer and T. A. Ciulla, “Pharmacotherapy for diabetic retinopathy,” Current Opinion in Ophthalmology, vol. 15, no. 6, pp. 508–518, 2004.
- R. Grigorian, N. Bhagat, P. Lanzetta, A. Tutela, and M. Zarbin, “Pars plana vitrectomy for refractory diabetic macular edema,” Seminars in Ophthalmology, vol. 18, no. 3, pp. 116–120, 2003.
- E. T. Cunningham, Jr., A. P. Adamis, M. Altaweel et al., “A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema,” Ophthalmology, vol. 112, no. 10, pp. 1747–1757, 2005.
- C. Haritoglou, D. Kook, A. Neubauer et al., “Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema,” Retina, vol. 26, no. 9, pp. 999–1005, 2006.
- A. M. Joussen, V. Poulaki, M. L. Le et al., “A central role for inflammation in the pathogenesis of diabetic retinopathy,” The FASEB Journal, vol. 18, no. 12, pp. 1450–1452, 2004.
- K. Miyamoto and Y. Ogura, “Pathogenetic potential of leukocytes in diabetic retinopathy,” Seminars in Ophthalmology, vol. 14, no. 4, pp. 233–239, 1999.
- D. S. McLeod, D. J. Lefer, C. Merges, and G. A. Lutty, “Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid,” American Journal of Pathology, vol. 147, no. 3, pp. 642–653, 1995.
- H. Funatsu, H. Yamashita, T. Ikeda, T. Mimura, S. Eguchi, and S. Hori, “Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema,” Ophthalmology, vol. 110, no. 9, pp. 1690–1696, 2003.
- K. Miyamoto, S. Khosrof, S.-E. Bursell et al., “Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 19, pp. 10836–10841, 1999.
- A. M. Joussen, V. Poulaki, W. Qin et al., “Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo,” American Journal of Pathology, vol. 160, no. 2, pp. 501–509, 2002.
- K. Miyamoto, S. Khosrof, S.-E. Bursell et al., “Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1),” American Journal of Pathology, vol. 156, no. 5, pp. 1733–1739, 2000.
- A. M. Joussen, T. Murata, A. Tsujikawa, B. Kirchhof, S.-E. Bursell, and A. P. Adamis, “Leukocyte-mediated endothelial cell injury and death in the diabetic retina,” American Journal of Pathology, vol. 158, no. 1, pp. 147–152, 2001.
- A. Nakajima, K. Wada, H. Miki et al., “Endogenous mediates anti-inflammatory activity in murine ischemia-reperfusion injury,” Gastroenterology, vol. 120, no. 2, pp. 460–469, 2001.
- W. Chen, W. J. Esselman, D. B. Jump, and J. V. Busik, “Anti-inflammatory effect of docosahexaenoic acid on cytokine-induced adhesion molecule expression in human retinal vascular endothelial cells,” Investigative Ophthalmology & Visual Science, vol. 46, no. 11, pp. 4342–4347, 2005.
- A. M. Joussen, V. Poulaki, N. Mitsiades et al., “Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF- suppression,” The FASEB Journal, vol. 16, no. 3, pp. 438–440, 2002.
- E. D. Rosen and B. M. Spiegelman, “: a nuclear regulator of metabolism, differentiation, and cell growth,” Journal of Biological Chemistry, vol. 276, no. 41, pp. 37731–37734, 2001.
- M. Okada, S. F. Yan, and D. J. Pinsky, “Peroxisome proliferator-activated receptor- () activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets,” The FASEB Journal, vol. 16, no. 14, pp. 1861–1868, 2002.
- V. Pasceri, H. D. Wu, J. T. Willerson, and E. T. Yeh, “Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor- activators,” Circulation, vol. 101, no. 3, pp. 235–238, 2000.
- C. Wang, M. Fu, M. D'Amico et al., “Inhibition of cellular proliferation through IB kinase-independent and peroxisome proliferator-activated receptor -dependent repression of cyclin D1,” Molecular and Cellular Biology, vol. 21, no. 9, pp. 3057–3070, 2001.
- K. Muranaka, Y. Yanagi, Y. Tamaki et al., “Effects of peroxisome proliferator-activated receptor and its ligand on blood-retinal barrier in a streptozotocin-induced diabetic model,” Investigative Ophthalmology & Visual Science, vol. 47, no. 10, pp. 4547–4552, 2006.
Copyright © 2008 Yasuo Yanagi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.