endothelin-1 and Retinal-Perforations

Imbalance between extracellular matrix protein synthesis and degradation is a key feature of diabetic retinopathy. Fibronectin, a predominant constituent of the extracellular matrix, has been shown to undergo alternative splicing to produce embryonic isoforms in various pathologic conditions, such as fibrotic diseases and tumorigenesis. Two such isoforms, oncofetal fibronectin variants that are characterized by the inclusion of the oncofetal domains A and B, were the focus of the present study.. The expression of oncofetal fibronectin variants was determined in human vitreous samples obtained from patients undergoing vitrectomy for proliferative diabetic retinopathy and nondiabetes-associated ocular conditions such as macular hole. In addition, an animal model of chronic diabetes and cultured endothelial cells was used to elucidate the mechanistic basis for this aberrant expression of oncofetal fibronectin.. Expression of fibronectin containing the oncofetal domain B was upregulated in the vitreous of patients with diabetic retinopathy.. Use of a well-established animal model of chronic diabetic complications and cultured endothelial cells showed that diabetes-induced upregulation of oncofetal fibronectin is, in part, dependent on hyperglycemia-induced transforming growth factor-beta1 and endothelin-1. Furthermore, the data suggest that oncofetal fibronectin is involved in endothelial cell proliferation.

Topics: Aged; Animals; Blotting, Western; Bosentan; Cell Division; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Endothelin-1; Endothelium, Vascular; Female; Fibronectins; Gene Silencing; Humans; Male; Middle Aged; Rats; Rats, Sprague-Dawley; Retinal Perforations; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation; Vitrectomy; Vitreous Body

Overproduction of endothelin-1 (ET-1) and nitric oxide (NO) in the retina is demonstrated in experimental diabetic animals. To clarify the possible involvement of ET-1 and NO in the pathogenesis of diabetic retinopathy, the authors examined the vitreous levels of these principal endothelium-derived vasoactive substances in patients with proliferative diabetic retinopathy (PDR).. Vitreous fluid was taken from patients with PDR (ET-1, n = 12; NO, n = 12) and from patients with macular holes as controls (ET-1, n = 10; NO, n = 10) at vitreous surgery. Endothelin-1 and NO metabolites were measured by radioimmunoassay and high-performance liquid chromatography based on the Griess method, respectively.. Endothelin-1 levels (mean +/- SE) were 21.5 +/- 1.7 pg/mL in the vitreous of patients with PDR and 16.7 +/- 0.7 pg/mL in the vitreous of patients with macular hole. There was a significant difference between patients with PDR and controls (P = 0.009, Mann-Whitney). Nitrate (NO3) was 49.8 +/- 5.0 micromol/L in patients with PDR and 24.2 +/- 2.8 micromol/L in patients with macula hole; it was also significantly elevated in patients with PDR (P = 0.004, Mann-Whitney), whereas nitrite (NO2) was not detected in this study.. These results indicate that ET-1 and NO may be related in the pathogenesis of PDR.

Topics: Adult; Aged; Aged, 80 and over; Chromatography, High Pressure Liquid; Diabetic Retinopathy; Endothelin-1; Female; Humans; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Radioimmunoassay; Retinal Perforations; Vitreous Body