Diabetic retinopathy (DR) remains as the leading cause of blindness among working age individuals in developed countries. Current treatments for DR (laser photocoagulation, intravitreal corticosteroids, intravitreal anti-VEGF agents, and vitreoretinal surgery) are applicable only at advanced stages of the disease and are associated with significant adverse effects. Therefore, new pharmacological treatments for the early stages of the disease are needed. Emerging evidence indicates that peroxisome proliferator-activator receptors (PPARs) agonists (in particular PPARα) are useful for the treatment of DR. However, the underlying molecular mechanisms are far from being elucidated. This paper mainly focuses on PPARs expression in the diabetic eye, its molecular implications, and the effect of PPAR agonists as a new approach for the treatment of DR. The availability of this new strategy will not only be beneficial in treating DR but may also result in a shift towards treating earlier stages of diabetic retinopathy, thus easing the burden of this devastating disease (Cheung et al. (2010)). 1. Introduction Diabetic retinopathy is the most common complication of diabetes, and proliferative diabetic retinopathy (PDR) remains the leading cause of blindness among working-age individuals in developed countries [1]. Diabetic macular edema (DME), another important event that occurs in diabetic retinopathy, is more frequent in type 2 than type 1 diabetes [2]. Although PDR is the most common sight-threatening lesion in type 1 diabetes, DME is the primary cause of poor visual acuity in type 2 diabetes. Because of the high prevalence of type 2 diabetes, DME is the main cause of visual impairment for diabetic patients. In addition, DME is almost invariably present when PDR is detected in type 2 diabetes [3]. Despite heterogeneity in patient selection criteria, country and selection period, the prevalence of patients with DR in Western countries is relatively similar, ranging from 21.9 to 36.8% [4]. Population-based studies suggest that about one-third of the diabetic population have signs of DR and one-tenth have vision-threatening states of retinopathy such as diabetic maculae edema (DME) and proliferative diabetic retinopathy (PDR) [5, 6]. Neovascularization caused by severe hypoxia is the hallmark of PDR, whereas vascular leakage caused by the breakdown of the blood retinal barrier (BRB) is the main event involved in the pathogenesis of DME. Healthcare costs for patients with DR are almost double than that of patients without it and they increase considerably with the
References
[1]
N. Cheung, P. Mitchell, and T. Y. Wong, “Diabetic retinopathy,” The Lancet, vol. 376, no. 9735, pp. 124–136, 2010.
[2]
R. Klein, S. E. Moss, B. E. K. Klein, M. D. Davis, and D. L. DeMets, “Wisconsin epidemiologic study of diabetic retinopathy. XII. Relationship of C-peptide and diabetic retinopathy,” Diabetes, vol. 39, no. 11, pp. 1445–1450, 1990.
[3]
L. Tong, S. A. Vernon, W. Kiel, V. Sung, and G. M. Orr, “Association of macular involvement with proliferative retinopathy in type 2 diabetes,” Diabetic Medicine, vol. 18, no. 5, pp. 388–394, 2001.
[4]
C. Delcourt, P. Massin, and M. Rosilio, “Epidemiology of diabetic retinopathy: expected vs reported prevalence of cases in the French population,” Diabetes and Metabolism, vol. 35, no. 6, pp. 431–438, 2009.
[5]
E. Chen, M. Looman, M. Laouri et al., “Burden of illness of diabetic macular edema: literature review,” Current Medical Research and Opinion, vol. 26, no. 7, pp. 1587–1597, 2010.
[6]
E. L. Lamoureux and T. Y. Wong, “Diabetic retinopathy in 2011: further insights from new epidemiological studies and clinical trials,” Diabetes Care, vol. 34, no. 4, pp. 1066–1067, 2011.
[7]
L. J. Lee, A. P. Yu, K. E. Cahill et al., “Direct and indirect costs among employees with diabetic retinopathy in the United States,” Current Medical Research and Opinion, vol. 24, no. 5, pp. 1549–1559, 2008.
[8]
E. M. Pelletier, B. Shim, R. Ben-Joseph, and J. J. Caro, “Economic outcomes associated with microvascular complications of type 2 diabetes mellitus: results from a US claims data analysis,” Pharmacoeconomics, vol. 27, no. 6, pp. 479–490, 2009.
[9]
E. Heintz, A. B. Wirehn, B. B. Peebo, U. Rosenqvist, and L. A. Levin, “Prevalence and healthcare costs of diabetic retinopathy: a population-based register study in Sweden,” Diabetologia, vol. 53, no. 10, pp. 2147–2154, 2010.
[10]
Q. Mohamed, M. C. Gillies, and T. Y. Wong, “Management of diabetic retinopathy: a systematic review,” The Journal of the American Medical Association, vol. 298, no. 8, pp. 902–916, 2007.
[11]
R. Simó and C. Hernández, “Advances in the medical treatment of diabetic retinopathy,” Diabetes Care, vol. 32, no. 8, pp. 1556–1562, 2009.
[12]
M. C. Sugden, P. W. Caton, and M. J. Holness, “PPAR control: it's SIRTainly as easy as PGC,” Journal of Endocrinology, vol. 204, no. 2, pp. 93–104, 2010.
[13]
N. D. Lalwani, K. Alvares, and M. K. Reddy, “Peroxisome proliferator-binding protein: identification and partial characterization of nafenopin-, clofibric acid-, and ciprofibrate-binding proteins from rat liver,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 15, pp. 5242–5246, 1987.
[14]
N. D. Lalwani, W. E. Fahl, and J. K. Reddy, “Detection of a nafenopin binding protein in rat liver cytosol associated with the induction of peroxisome proliferation by hypolipidemic compounds,” Biochemical and Biophysical Research Communications, vol. 116, no. 2, pp. 388–393, 1983.
[15]
J. Vamecq and N. Latruffe, “Medical significance of peroxisome proliferator-activated receptors,” The Lancet, vol. 354, no. 9173, pp. 141–148, 1999.
[16]
R. M. Evans, “The steroid and thyroid hormone receptor superfamily,” Science, vol. 240, no. 4854, pp. 889–895, 1988.
[17]
L. Fajas, D. Auboeuf, E. Raspé et al., “The organization, promoter analysis, and expression of the human PPARγ gene,” The Journal of Biological Chemistry, vol. 272, no. 30, pp. 18779–18789, 1997.
[18]
O. Braissant, F. Foufelle, C. Scotto, M. Dau？a, and W. Wahli, “Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and -γ in the adult rat,” Endocrinology, vol. 137, no. 1, pp. 354–366, 1996.
[19]
D. Auboeuf, J. Rieusset, L. Fajas et al., “Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-α in humans: no alteration in adipose tissue of obese and NIDDM patients,” Diabetes, vol. 46, no. 8, pp. 1319–1327, 1997.
[20]
T. Lemberger, O. Braissant, C. Juge-Aubry et al., “PPAR tissue distribution and interactions with other hormone-signaling pathways,” Annals of the New York Academy of Sciences, vol. 804, pp. 231–251, 1996.
[21]
M. del V. Cano and P. L. Gehlbach, “PPAR-α ligands as potential therapeutic agents for wet age-related macular degeneration,” PPAR Research, vol. 2008, Article ID 821592, 5 pages, 2008.
[22]
D. Bishop-Bailey, “PPARs and angiogenesis,” Biochemical Society Transactions, vol. 39, pp. 1601–1605, 2011.
[23]
J. Zhou, K. M. Wilson, and J. D. Medh, “Genetic analysis of four novel peroxisome proliferator activated receptor-γ splice variants in monkey macrophages,” Biochemical and Biophysical Research Communications, vol. 293, no. 1, pp. 274–283, 2002.
[24]
G. Ding, M. Fu, Q. Qin et al., “Cardiac peroxisome proliferator-activated receptor γ is essential in protecting cardiomyocytes from oxidative damage,” Cardiovascular Research, vol. 76, no. 2, pp. 269–279, 2007.
[25]
A. W. Norris, L. Chen, S. J. Fisher et al., “Muscle-specific PPARγ-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones,” The Journal of Clinical Investigation, vol. 112, no. 4, pp. 608–618, 2003.
[26]
I. Issemann and S. Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,” Nature, vol. 347, no. 6294, pp. 645–650, 1990.
[27]
B. Desvergne and W. Wahli, “Peroxisome proliferator-activated receptors: nuclear control of metabolism,” Endocrine Reviews, vol. 20, no. 5, pp. 649–688, 1999.
[28]
D. M. Kendall, C. J. Rubin, P. Mohideen et al., “Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (α/γ) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a double-blind, randomized, pioglitazone-comparative study,” Diabetes Care, vol. 29, no. 5, pp. 1016–1023, 2006.
[29]
C. V. Rizos, M. S. Elisaf, D. P. Mikhailidis, and E. N. Liberopoulos, “How safe is the use of thiazolidinediones in clinical practice?” Expert Opinion on Drug Safety, vol. 8, no. 1, pp. 15–32, 2009.
[30]
S. E. Nissen, K. Wolski, and E. J. Topol, “Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus,” The Journal of the American Medical Association, vol. 294, no. 20, pp. 2581–2586, 2005.
[31]
R. E. Ratner, S. Parikh, and C. Tou, “Efficacy, safety and tolerability of tesaglitazar when added to the therapeutic regimen of poorly controlled insulin-treated patients with type 2 diabetes,” Diabetes and Vascular Disease Research, vol. 4, no. 3, pp. 214–221, 2007.
[32]
M. Dietz, P. Mohr, B. Kuhn et al., “Comparative molecular profiling of the PPARalpha/gamma activator aleglitazar: PPAR selectivity, activity and interaction with cofactors,” ChemMedChem, vol. 7, no. 6, pp. 1101–1111, 2012.
[33]
M. A. Cavender and A. M. Lincoff, “Therapeutic potential of aleglitazar, a new dual PPAR-alpha/gamma agonist: implications for cardiovascular disease in patients with diabetes mellitus,” American Journal of Cardiovascular Drugs, vol. 10, no. 4, pp. 209–216, 2010.
[34]
H. A. Pershadsingh and D. M. Moore, “PPARγ agonists: potential as therapeutics for neovascular retinopathies,” PPAR Research, vol. 2008, Article ID 164273, 13 pages, 2008.
[35]
I. Imayama, T. Ichiki, K. Inanaga et al., “Telmisartan downregulates angiotensin II type 1 receptor through activation of peroxisome proliferator-activated receptor γ,” Cardiovascular Research, vol. 72, no. 1, pp. 184–190, 2006.
[36]
D. V. Erbe, K. Gartrell, Y. L. Zhang et al., “Molecular activation of PPARγ by angiotensin II type 1-receptor antagonists,” Vascular Pharmacology, vol. 45, no. 3, pp. 154–162, 2006.
[37]
B. Cariou, Y. Zair, B. Staels, and E. Bruckert, “Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism,” Diabetes Care, vol. 34, no. 9, pp. 2008–2014, 2011.
[38]
A. A. Herzlich, X. Ding, D. Shen, R. J. Ross, J. Tuo, and C. C. Chan, “Peroxisome proliferator-activated receptor expression in murine models and humans with age-related macular degeneration,” The Open Biology Journal, vol. 2, pp. 141–148, 2009.
[39]
M. A. Dwyer, D. Kazmin, P. Hu, D. P. McDonnell, and G. Malek, “Research resource: nuclear receptor atlas of human retinal pigment epithelial cells: potential relevance to age-related macular degeneration,” Molecular Endocrinology, vol. 25, no. 2, pp. 360–372, 2011.
[40]
S. Qin, A. P. McLaughlin, and G. W. De Vries, “Protection of RPE cells from oxidative injury by 15-deoxy-Δ 12,14-prostaglandin J2 by augmenting GSH and activating MAPK,” Investigative Ophthalmology & Visual Science, vol. 47, no. 11, pp. 5098–5105, 2006.
[41]
F. Wang, L. Gao, B. Gong et al., “Tissue-specific expression of PPAR mRNAs in diabetic rats and divergent effects of cilostazol,” Canadian Journal of Physiology and Pharmacology, vol. 86, no. 7, pp. 465–471, 2008.
[42]
A. Tawfik, T. Sanders, K. Kahook, S. Akeel, A. Elmarakby, and M. Al-Shabrawey, “Suppression of retinal peroxisome proliferator-activated receptor γ in experimental diabetes and oxygen-induced retinopathy: role of NADPH oxidase,” Investigative Ophthalmology & Visual Science, vol. 50, no. 2, pp. 878–884, 2009.
[43]
V. Costa, A. Casamassimi, K. Esposito et al., “Characterization of a novel polymorphism in PPARG regulatory region associated with type 2 diabetes and diabetic retinopathy in Italy,” Journal of Biomedicine and Biotechnology, vol. 2009, Article ID 126917, 7 pages, 2009.
[44]
M. G. Petrovi？, T. Kunej, B. Peterlin, P. Dov？, and D. Petrovi？, “Gly482Ser polymorphism of the peroxisome proliferator-activated receptor-γ coactivator-1 gene might be a risk factor for diabetic retinopathy in Slovene population (Caucasians) with type 2 diabetes and the Pro12Ala polymorphism of the PPARγ gene is not,” Diabetes/Metabolism Research and Reviews, vol. 21, no. 5, pp. 470–474, 2005.
[45]
C. Hernandez and R. Simo, “Neuroprotection in diabetic retinopathy,” Current Diabetes Reports, vol. 12, no. 4, pp. 329–337, 2012.
[46]
R. Simo and C. Hernandez, “Neurodegeneration is an early event in diabetic retinopathy: therapeutic implications,” British Journal of Ophthalmology, vol. 96, no. 10, pp. 1285–1290, 2012.
[47]
E. Carrasco, C. Hernández, A. Miralles, P. Huguet, J. Farrés, and R. Simó, “Lower somatostatin expression is an early event in diabetic retinopathy and is associated with retinal neurodegeneration,” Diabetes Care, vol. 30, no. 11, pp. 2902–2908, 2007.
[48]
M. Garcia-Ramírez, C. Hernández, M. Villarroel et al., “Interphotoreceptor retinoid-binding protein (IRBP) is downregulated at early stages of diabetic retinopathy,” Diabetologia, vol. 52, no. 12, pp. 2633–2641, 2009.
[49]
H. W. van Dijk, F. D. Verbraak, P. H. B. Kok et al., “Decreased retinal ganglion cell layer thickness in patients with type 1 diabetes,” Investigative Ophthalmology & Visual Science, vol. 51, no. 7, pp. 3660–3665, 2010.
[50]
E. Rungger-Br？ndle, A. A. Dosso, and P. M. Leuenberger, “Glial reactivity, an early feature of diabetic retinopathy,” Investigative Ophthalmology & Visual Science, vol. 41, no. 7, pp. 1971–1980, 2000.
[51]
C. Gerhardinger, M. B. Costa, M. C. Coulombe, I. Toth, T. Hoehn, and P. Grosu, “Expression of acute-phase response proteins in retinal Müller cells in diabetes,” Investigative Ophthalmology & Visual Science, vol. 46, no. 1, pp. 349–357, 2005.
[52]
E. Lieth, A. J. Barber, B. Xu et al., “Glial reactivity and impaired glutamate metabolism in short- term experimental diabetic retinopathy. Penn State Retina Research Group,” Diabetes, vol. 47, pp. 815–820, 1998.
[53]
E. Lieth, K. F. LaNoue, D. A. Antonetti, and M. Ratz, “Diabetes reduces glutamate oxidation and glutamine synthesis in the retina. The Penn State Retina Research Group,” Experimental Eye Research, vol. 70, no. 6, pp. 723–730, 2000.
[54]
R. A. Kowluru, R. L. Engerman, G. L. Case, and T. S. Kern, “Retinal glutamate in diabetes and effect of antioxidants,” Neurochemistry International, vol. 38, no. 5, pp. 385–390, 2001.
[55]
J. E. Pulido, J. S. Pulido, J. C. Erie et al., “A role for excitatory amino acids in diabetic eye disease,” Experimental Diabesity Research, vol. 2007, Article ID 36150, 7 pages, 2007.
[56]
Y. K. Ng, X. X. Zeng, and E. A. Ling, “Expression of glutamate receptors and calcium-binding proteins in the retina of streptozotocin-induced diabetic rats,” Brain Research, vol. 1018, no. 1, pp. 66–72, 2004.
[57]
A. R. Santiago, J. M. Gaspar, F. I. Baptista et al., “Diabetes changes the levels of ionotropic glutamate receptors in the rat retina,” Molecular Vision, vol. 15, pp. 1620–1630, 2009.
[58]
P. Aoun, J. W. Simpkins, and N. Agarwal, “Role of PPAR-γ ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells,” Investigative Ophthalmology & Visual Science, vol. 44, no. 7, pp. 2999–3004, 2003.
[59]
A. Bernardo, G. Levi, and L. Minghetti, “Role of the peroxisome proliferator-activated receptor-γ (PPAR-γ) and its natural ligand 15-deoxy-Δ(12,14)-prostaglandin J2 in the regulation of microglial functions,” European Journal of Neuroscience, vol. 12, no. 7, pp. 2215–2223, 2000.
[60]
A. Bernardo, M. A. Ajmone-Cat, L. Gasparini, E. Ongini, and L. Minghetti, “Nuclear receptor peroxisome proliferator-activated receptor-γ is activated in rat microglial cells by the anti-inflammatory drug HCT1026, a derivative of flurbiprofen,” Journal of Neurochemistry, vol. 92, no. 4, pp. 895–903, 2005.
[61]
P. Li, X. Xu, Z. Zheng, B. Zhu, Y. Shi, and K. Liu, “Protective effects of rosiglitazone on retinal neuronal damage in diabetic rats,” Current Eye Research, vol. 36, no. 7, pp. 673–679, 2011.
[62]
E. L. Fletcher, J. A. Phipps, M. M. Ward, K. A. Vessey, and J. L. Wilkinson-Berka, “The renin-angiotensin system in retinal health and disease: its influence on neurons, glia and the vasculature,” Progress in Retinal and Eye Research, vol. 29, no. 4, pp. 284–311, 2010.
[63]
S. Sarlos and J. L. Wilkinson-Berka, “The renin-angiotensin system and the developing retinal vasculature,” Investigative Ophthalmology & Visual Science, vol. 46, no. 3, pp. 1069–1077, 2005.
[64]
N. Nagai, K. Noda, T. Urano et al., “Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor,” Investigative Ophthalmology & Visual Science, vol. 46, no. 3, pp. 1078–1084, 2005.
[65]
M. Schupp, J. Janke, R. Clasen, T. Unger, and U. Kintscher, “Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-γ activity,” Circulation, vol. 109, no. 17, pp. 2054–2057, 2004.
[66]
R. Simó, M. Villarroel, L. Corraliza, C. Hernández, and M. Garcia-Ramírez, “The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier—implications for the pathogenesis of diabetic retinopathy,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 190724, 15 pages, 2010.
[67]
A. V. Ershov and N. G. Bazan, “Photoreceptor phagocytosis selectively activates PPARgamma expression in retinal pigment epithelial cells,” Journal of Neuroscience Research, vol. 60, pp. 328–337, 2000.
[68]
N. Toda and M. Nakanishi-Toda, “Nitric oxide: ocular blood flow, glaucoma, and diabetic retinopathy,” Progress in Retinal and Eye Research, vol. 26, no. 3, pp. 205–238, 2007.
[69]
A. Ergul, “Endothelin-1 and diabetic complications: focus on the vasculature,” Pharmacological Research, vol. 63, no. 6, pp. 477–482, 2011.
[70]
J. Kim, Y. S. Oh, and S. H. Shinn, “Troglitazone reverses the inhibition of nitric oxide production by high glucose in cultured bovine retinal pericytes,” Experimental Eye Research, vol. 81, no. 1, pp. 65–70, 2005.
[71]
T. Omae, T. Nagaoka, I. Tanano, and A. Yoshida, “Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, induces dilation of isolated porcine retinal arterioles: role of nitric oxide and potassium channels,” Investigative Ophthalmology & Visual Science, vol. 52, no. 9, pp. 6749–6756, 2011.
[72]
H. Satoh, K. Tsukamoto, Y. Hashimoto et al., “Thiazolidinediones suppress endothelin-1 secretion from bovine vascular endothelial cells: a new possible role of PPARγ on vascular endothelial function,” Biochemical and Biophysical Research Communications, vol. 254, no. 3, pp. 757–763, 1999.
[73]
D. Ray, M. Mishra, S. Ralph, I. Read, R. Davies, and P. Brenchley, “Association of the VEGF gene with proliferative diabetic retinopathy but not proteinuria in diabetes,” Diabetes, vol. 53, no. 3, pp. 861–864, 2004.
[74]
M. Colucciello, “Vision loss due to macular edema induced by rosiglitazone treatment of diabetes mellitus,” Archives of Ophthalmology, vol. 123, no. 9, pp. 1273–1275, 2005.
[75]
E. H. Ryan Jr., D. P. Han, R. C. Ramsay et al., “Diabetic macular edema associated with glitazone use,” Retina, vol. 26, no. 5, pp. 562–570, 2006.
[76]
N. V. Niemeyer and L. M. Janney, “Thiazolidinedione-induced edema,” Pharmacotherapy, vol. 22, no. 7, pp. 924–929, 2002.
[77]
D. S. Fong and R. Contreras, “Glitazone use associated with diabetic macular edema,” American Journal of Ophthalmology, vol. 147, no. 4, pp. 583.e1–586.e1, 2009.
[78]
I. Idris, G. Warren, and R. Donnelly, “Association between thiazolidinedione treatment and risk of macular edema among patients with type 2 diabetes,” Archives of Internal Medicine, vol. 172, no. 13, pp. 1005–1011, 2012.
[79]
W. T. Ambrosius, R. P. Danis, D. C. Goff Jr. et al., “Lack of association between thiazolidinediones and macular edema in type 2 diabetes: the ACCORD eye substudy,” Archives of Ophthalmology, vol. 128, no. 3, pp. 312–318, 2010.
[80]
M. Colucciello and E. Ryan, “Macular edema and thiazolidinediones,” Archives of Ophthalmology, vol. 128, no. 12, pp. 1630–1631, 2010.
[81]
K. Muranaka, Y. Yanagi, Y. Tamaki et al., “Effects of peroxisome proliferator-activated receptor γ 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.
[82]
Z. Zheng, H. Chen, H. Wang et al., “Improvement of retinal vascular injury in diabetic rats by statins is associated with the inhibition of mitochondrial reactive oxygen species pathway mediated by peroxisome proliferator-activated receptor γ coactivator 1α,” Diabetes, vol. 59, no. 9, pp. 2315–2325, 2010.
[83]
D. K. Coletta, A. Sriwijitkamol, E. Wajcberg et al., “Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial,” Diabetologia, vol. 52, no. 4, pp. 723–732, 2009.
[84]
K. Yamakawa, M. Hosoi, H. Koyama et al., “Peroxisome proliferator-activated receptor-γ agonists increase vascular endothelial growth factor expression in human vascular smooth muscle cells,” Biochemical and Biophysical Research Communications, vol. 271, no. 3, pp. 571–574, 2000.
[85]
M. Emoto, T. Anno, Y. Sato et al., “Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes,” Diabetes, vol. 50, no. 5, pp. 1166–1170, 2001.
[86]
V. Chintalgattu, G. S. Harris, S. M. Akula, and L. C. Katwa, “PPAR-γ agonists induce the expression of VEGF and its receptors in cultured cardiac myofibroblasts,” Cardiovascular Research, vol. 74, no. 1, pp. 140–150, 2007.
[87]
T. Murata, Y. Hata, T. Ishibashi et al., “Response of experimental retinal neovascularization to thiazolidinediones,” Archives of Ophthalmology, vol. 119, no. 5, pp. 709–717, 2001.
[88]
A. Aljada, L. O'Connor, Y. Y. Fu, and S. A. Mousa, “PPARγ ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis,” Angiogenesis, vol. 11, no. 4, pp. 361–367, 2008.
[89]
A. Higuchi, K. Ohashi, R. Shibata, S. Sono-Romanelli, K. Walsh, and N. Ouchi, “Thiazolidinediones reduce pathological neovascularization in ischemic retina via an adiponectin-dependent mechanism,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 1, pp. 46–53, 2010.
[90]
G. A. Rodrigues, F. Maurier-Mahé, D. L. Shurland et al., “Differential effects of PPARγ ligands on oxidative stress-induced death of retinal pigmented epithelial cells,” Investigative Ophthalmology & Visual Science, vol. 52, no. 2, pp. 890–903, 2011.
[91]
H. Hatanaka, N. Koizumi, N. Okumura, et al., “Epithelial-mesenchymal transition-like phenotypic changes of retinal pigment epithelium induced by TGF-β are prevented by PPAR-γ agonists,” Investigative Ophthalmology & Visual Science, vol. 53, no. 11, pp. 6955–6963, 2012.
[92]
L. Q. Shen, A. Child, G. M. Weber, J. Folkman, and L. P. Aiello, “Rosiglitazone and delayed onset of proliferative diabetic retinopathy,” Archives of Ophthalmology, vol. 126, no. 6, pp. 793–799, 2008.
[93]
V. Pasceri, H. D. Wu, J. T. Willerson, and E. T. H. Yeh, “Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-γ activators,” Circulation, vol. 101, no. 3, pp. 235–238, 2000.
[94]
M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998.
[95]
H. Shu, B. Wong, G. Zhou et al., “Activation of PPARα or γ reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells,” Biochemical and Biophysical Research Communications, vol. 267, no. 1, pp. 345–349, 2000.
[96]
T. Ishizuka, S. Itaya, H. Wada et al., “Differential effect of the antidiabetic thiazolidinediones troglitazone and pioglitazone on human platelet aggregation mechanism,” Diabetes, vol. 47, no. 9, pp. 1494–1500, 1998.
[97]
B. P. Harrold, V. J. Marmion, and K. R. Gough, “A double-blind controlled trial of clofibrate in the treatment of diabetic retinopathy,” Diabetes, vol. 18, no. 5, pp. 285–291, 1969.
[98]
P. A. Dorne, “Exudative diabetic retinopathy. The use of clofibrate in the treatment of hard exudates using a reduced but prolonged dosage over several years,” Archives d'Ophtalmologie, vol. 37, no. 5, pp. 393–400, 1977.
[99]
A. Keech, R. J. Simes, P. Barter et al., “Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial,” The Lancet, vol. 366, no. 9500, pp. 1849–1861, 2005.
[100]
A. C. Keech, P. Mitchell, P. A. Summanen et al., “Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial,” The Lancet, vol. 370, no. 9600, pp. 1687–1697, 2007.
[101]
E. Y. Chew, W. T. Ambrosius, M. D. Davis et al., “Effects of medical therapies on retinopathy progression in type 2 diabetes,” The New England Journal of Medicine, vol. 363, no. 3, pp. 233–244, 2010.
[102]
R. Simó and C. Hernández, “Fenofibrate for diabetic retinopathy,” The Lancet, vol. 370, no. 9600, pp. 1667–1668, 2007.
[103]
H. N. Ginsberg, M. B. Elam, L. C. Lovato et al., “Effects of combination lipid therapy in type 2 diabetes mellitus,” The New England Journal of Medicine, vol. 362, no. 17, pp. 1563–1574, 2010.
[104]
M. García-Ramírez, F. Canals, C. Hernández et al., “Proteomic analysis of human vitreous fluid by fluorescence-based difference gel electrophoresis (DIGE): a new strategy for identifying potential candidates in the pathogenesis of proliferative diabetic retinopathy,” Diabetologia, vol. 50, no. 6, pp. 1294–1303, 2007.
[105]
R. Simo, M. Garcia-Ramirez, M. Higuera, and C. Hernandez, “Apolipoprotein A1 is overexpressed in the retina of diabetic patients,” American Journal of Ophthalmology, vol. 147, no. 2, pp. 319.e1–325.e1, 2009.
[106]
B. Staels, J. Dallongeville, J. Auwerx, K. Schoonjans, E. Leitersdorf, and J. C. Fruchart, “Mechanism of action of fibrates on lipid and lipoprotein metabolism,” Circulation, vol. 98, no. 19, pp. 2088–2093, 1998.
[107]
R. Arakawa, N. Tamehiro, T. Nishimaki-Mogami, K. Ueda, and S. Yokoyama, “Fenofibric acid, an active form of fenofibrate, increases apolipoprotein A-I-mediated high-density lipoprotein biogenesis by enhancing transcription of ATP-binding cassette transporter A1 gene in a liver X receptor-dependent manner,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 6, pp. 1193–1197, 2005.
[108]
M. B. Sasongko, T. Y. Wong, T. T. Nguyen, J. E. Shaw, A. J. Jenkins, and J. J. Wang, “Novel versus traditional risk markers for diabetic retinopathy,” Diabetologia, vol. 55, no. 3, pp. 666–670, 2012.
[109]
R. Bordet, T. Ouk, O. Petrault et al., “PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases,” Biochemical Society Transactions, vol. 34, no. 6, pp. 1341–1346, 2006.
[110]
H. Murakami, R. Murakami, F. Kambe et al., “Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC,” Biochemical and Biophysical Research Communications, vol. 341, no. 4, pp. 973–978, 2006.
[111]
M. Zanetti, A. Stocca, B. Dapas et al., “Inhibitory effects of fenofibrate on apoptosis and cell proliferation in human endothelial cells in high glucose,” Journal of Molecular Medicine, vol. 86, no. 2, pp. 185–195, 2008.
[112]
A. Tomizawa, Y. Hattori, T. Inoue, S. Hattori, and K. Kasai, “Fenofibrate suppresses microvascular inflammation and apoptosis through adenosine monophosphate-activated protein kinase activation,” Metabolism, vol. 60, no. 4, pp. 513–522, 2011.
[113]
J. Kim, J. H. Ahn, J. H. Kim et al., “Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway,” Experimental Eye Research, vol. 84, no. 5, pp. 886–893, 2007.
[114]
S. Miranda, A. Gonzalez-Rodriguez, M. Garcia-Ramirez et al., “Beneficial effects of fenofibrate in retinal pigment epithelium by the modulation of stress and survival signaling under diabetic conditions,” Journal of Cellular Physiology, vol. 227, no. 6, pp. 2352–2362, 2012.
[115]
D. A. Antonetti, R. Klein, and T. W. Gardner, “Diabetic retinopathy,” The New England Journal of Medicine, vol. 366, pp. 1227–1239, 2012.
[116]
G. Chinetti, S. Griglio, M. Antonucci et al., “Activation of proliferator-activated receptors α and γ induces apoptosis of human monocyte-derived macrophages,” The Journal of Biological Chemistry, vol. 273, no. 40, pp. 25573–25580, 1998.
[117]
Z. Israelian-Konaraki and P. D. Reaven, “Peroxisome proliferator-activated receptor-alpha and atherosclerosis: from basic mechanisms to clinical implications,” Cardiology, vol. 103, no. 1, pp. 1–9, 2005.
[118]
M. Villarroel, M. Garcia-Ramirez, L. Corraliza, C. Hernandez, and R. Simo, “Fenofibric acid prevents retinal pigment epithelium disruption induced by interleukin-1beta by suppressing AMP-activated protein kinase (AMPK) activation,” Diabetologia, vol. 54, no. 6, pp. 1543–1553, 2011.
[119]
K. Trudeau, S. Roy, W. Guo et al., “Fenofibric acid reduces fibronectin and collagen type IV overexpression in human retinal pigment epithelial cells grown in conditions mimicking the diabetic milieu: functional implications in retinal permeability,” Investigative Ophthalmology & Visual Science, vol. 52, pp. 6348–6354, 2011.
[120]
I. Inoue, K. Shino, S. Noji, T. Awata, and S. Katayama, “Expression of peroxisome proliferator-activated receptor α (PPARα) in primary cultures of human vascular endothelial cells,” Biochemical and Biophysical Research Communications, vol. 246, no. 2, pp. 370–374, 1998.
[121]
M. Meissner, M. Stein, C. Urbich et al., “PPARα activators inhibit vascular endothelial growth factor receptor-2 expression by repressing Sp1-dependent DNA binding and transactivation,” Circulation Research, vol. 94, no. 3, pp. 324–332, 2004.
[122]
J. Varet, L. Vincent, P. Mirshahi et al., “Fenofibrate inhibits angiogenesis in vitro and in vivo,” Cellular and Molecular Life Sciences, vol. 60, no. 4, pp. 810–819, 2003.
[123]
Y. Yokoyama, B. Xin, T. Shigeto et al., “Clofibric acid, a peroxisome proliferator-activated receptor α ligand, inhibits growth of human ovarian cancer,” Molecular Cancer Therapeutics, vol. 6, no. 4, pp. 1379–1386, 2007.
[124]
Y. Chen, Y. Hu, M. Lin et al., “Therapeutic effects of PPARalpha agonists on diabetic retinopathy in type 1 diabetes models,” Diabetes, vol. 62, no. 1, pp. 261–272, 2013.
[125]
R. L. Stephen, M. C. U. Gustafsson, M. Jarvis et al., “Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines,” Cancer Research, vol. 64, no. 9, pp. 3162–3170, 2004.
