Effects of peroxisome proliferator-activated receptor gamma and its ligand on blood-retinal barrier in a streptozotocin-induced diabetic model.

PURPOSE To clarify whether endogenous peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligand, rosiglitazone, affect retinal leukostasis and the associated vascular leakage using an experimental diabetic model. METHODS Diabetes was induced in heterozygous PPARgamma+/- mice and Brown Norway rats with an intraperitoneal streptozotocin (STZ) injection. Retinal leukostasis and leakage, quantified by concanavalin A (Con A) lectin perfusion labeling combined with a fluorophotometric dextran leakage assay, were investigated at 120 days in diabetic PPARgamma+/- and wild-type mice and at 21 days in diabetic rats receiving rosiglitazone or the vehicle. The retinal protein expression levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-alpha, and the intercellular adhesion molecule (ICAM)-1 were investigated by means of the ELISA assay. RESULTS In the diabetic PPARgamma+/- mice, retinal leukostasis and leakage were greater than in the diabetic wild-type mice. In addition retinal leukostasis and leakage were suppressed by treatment with rosiglitazone in experimental diabetic rats. ELISA analysis revealed that the upregulated ICAM-1 expression in the diabetic rat retina was reduced by rosiglitazone treatment. CONCLUSIONS An endogenous pathway involving PPARgamma provides protection against retinal leukostasis and retinal leakage in diabetes and treatment with PPARgamma specific ligands inhibits retinal leukostasis and retinal leakage in diabetic rats.

[1]  K Miyamoto,et al.  In vivo demonstration of increased leukocyte entrapment in retinal microcirculation of diabetic rats. , 1998, Investigative ophthalmology & visual science.

[2]  K. Yamashiro,et al.  VEGF164 is proinflammatory in the diabetic retina. , 2003, Investigative ophthalmology & visual science.

[3]  L. Aiello,et al.  Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  E. Agrón,et al.  Serum inflammatory markers in diabetic retinopathy. , 2005, Investigative ophthalmology & visual science.

[5]  P. Jap,et al.  Protein synthesis in bovine and human nuclear fiber cells. , 1985, Experimental eye research.

[6]  A. Valledor,et al.  Nuclear receptor signaling in macrophages. , 2004, Biochemical pharmacology.

[7]  V. Pasceri,et al.  Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. , 2000, Circulation.

[8]  B. Spiegelman,et al.  PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. , 2001, The Journal of biological chemistry.

[9]  D. Lefer,et al.  Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. , 1995, The American journal of pathology.

[10]  Michael Brownlee,et al.  Inhibition of Cellular Proliferation through IκB Kinase-Independent and Peroxisome Proliferator-Activated Receptor γ-Dependent Repression of Cyclin D1 , 2001, Molecular and Cellular Biology.

[11]  A. Adamis,et al.  Is diabetic retinopathy an inflammatory disease? , 2002, The British journal of ophthalmology.

[12]  Bernd Kirchhof,et al.  Nonsteroidal anti‐inflammatory drugs prevent early diabetic retinopathy via TNF‐α suppression , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  Ulrich Schraermeyer,et al.  A central role for inflammation in the pathogenesis of diabetic retinopathy , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  Y. Terauchi,et al.  Endogenous PPAR gamma mediates anti-inflammatory activity in murine ischemia-reperfusion injury. , 2001, Gastroenterology.

[15]  K Miyamoto,et al.  Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). , 2000, The American journal of pathology.

[16]  W. Wahli,et al.  PPARs as drug targets to modulate inflammatory responses? , 2004, Current drug targets. Inflammation and allergy.

[17]  D. Pinsky,et al.  Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets. , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  H. Taylor,et al.  Age-specific causes of bilateral visual impairment. , 2000, Archives of ophthalmology.

[19]  Joan W. Miller,et al.  Expression of leukocyte adhesion molecules in human subfoveal choroidal neovascular membranes treated with and without photodynamic therapy. , 2004, Investigative ophthalmology & visual science.

[20]  G. Lutty,et al.  Relationship of polymorphonuclear leukocytes to capillary dropout in the human diabetic choroid. , 1997, The American journal of pathology.

[21]  Dallas Jones,et al.  Emerging roles of PPARS in inflammation and immunity , 2002, Nature Reviews Immunology.

[22]  Shuichi Yamamoto,et al.  Monocyte chemotactic protein-1 levels in the vitreous of patients with proliferative vitreoretinopathy. , 2002, Japanese journal of ophthalmology.

[23]  P. Wiedemann,et al.  Intercellular adhesion molecule-1 levels in plasma and vitreous from patients with vitreoretinal disorders. , 1995, German journal of ophthalmology.

[24]  V. Reppucci,et al.  Soluble cellular adhesion molecules in proliferative vitreoretinopathy and proliferative diabetic retinopathy. , 1999, Current eye research.

[25]  D. Pinsky,et al.  Peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) activation suppresses ischemic induction of Egr‐1 and its inflammatory gene targets , 2002 .

[26]  G. Yancopoulos,et al.  VEGF-initiated blood-retinal barrier breakdown in early diabetes. , 2001, Investigative ophthalmology & visual science.

[27]  A. Adamis,et al.  Sensitive blood-retinal barrier breakdown quantitation using Evans blue. , 2001, Investigative ophthalmology & visual science.

[28]  P. Tontonoz,et al.  PPARs in atherosclerosis: the clot thickens. , 2004, The Journal of clinical investigation.

[29]  V K Chatterjee,et al.  Inhibition of cellular proliferation through IkappaB kinase-independent and peroxisome proliferator-activated receptor gamma-dependent repression of cyclin D1. , 2001, Molecular and cellular biology.

[30]  Min-Seon Kim,et al.  Peroxisome Proliferator-Activated Receptor (PPAR)-α Activation Prevents Diabetes in OLETF Rats: Comparison With PPAR-γ Activation , 2003 .

[31]  Min-Seon Kim,et al.  Peroxisome proliferator-activated receptor (PPAR)-alpha activation prevents diabetes in OLETF rats: comparison with PPAR-gamma activation. , 2003, Diabetes.

[32]  B. Hoogwerf,et al.  Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. , 1996, Archives of ophthalmology.

[33]  Satoshi Tanaka,et al.  PPARγ Mediates High-Fat Diet–Induced Adipocyte Hypertrophy and Insulin Resistance , 1999 .

[34]  P. Campochiaro,et al.  Immunohistochemical localization of blood-retinal barrier breakdown in human diabetics. , 1989, The American journal of pathology.

[35]  J. Cunha-Vaz,et al.  Breakdown of the inner and outer blood retinal barrier in streptozotocin-induced diabetes. , 1998, Experimental eye research.

[36]  Bernd Kirchhof,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. , 2002, The American journal of pathology.

[37]  B. Spiegelman,et al.  PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth* , 2001, The Journal of Biological Chemistry.

[38]  M. Karin,et al.  Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. , 1997, The New England journal of medicine.

[39]  B Kirchhof,et al.  Leukocyte-mediated endothelial cell injury and death in the diabetic retina. , 2001, The American journal of pathology.

[40]  S. Aizawa,et al.  PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. , 1999, Molecular cell.

[41]  V. Ganapathy,et al.  Death of retinal neurons in streptozotocin-induced diabetic mice. , 2004, Investigative ophthalmology & visual science.

[42]  R. Klein,et al.  The 14-year incidence of visual loss in a diabetic population. , 1998, Ophthalmology.

[43]  Y. Terauchi,et al.  Endogenous PPARγ mediates anti-inflammatory activity in murine ischemia-reperfusion injury , 2001 .

[44]  K. Miyarnoto.  Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition , 1999 .