leptin and Retinal-Neovascularization

Diabetic retinopathy is the leading cause of new blindness in adults in developed countries. Leptin, an adipocyte-derived hormone, stimulates endothelial proliferation and angiogenesis. This study was designed to elucidate the pathophysiologic role of leptin in the progression of retinal neovascularization. Using the retinopathy of prematurity model, a mouse model of ischemia-induced retinal neovascularization, we have demonstrated more pronounced retinal neovascularization in 17-day-old transgenic mice overexpressing leptin than in age-matched wild-type littermates. Ischemia-induced retinal neovascularization was markedly suppressed in 17-day-old leptin-deficient ob/ob mice. Western blot analysis revealed that a biologically active leptin receptor isoform is expressed in mouse retinal endothelial cells. Leptin receptor expression was also detected in primary cultures of porcine retinal endothelial cells, where it upregulated vascular endothelial growth factor (VEGF) mRNA expression. This effect was thought to be mediated at least partly through the activation of signal transducers and activators of transcription (STAT)3, because adenoviral transfection of the dominant-negative form of STAT3 abolished the leptin-induced upregulation of VEGF mRNA expression in retinal endothelial cells. This study provides evidence that leptin stimulates the ischemia-induced retinal neovasucularization possibly through the upregulation of endothelial VEGF, thereby suggesting that leptin antagonism may offer a novel therapeutic strategy to prevent or treat diabetic retinopathy.

Topics: Animals; Diabetic Retinopathy; DNA-Binding Proteins; Female; Gene Expression; Ischemia; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxygen; Pregnancy; Receptors, Cell Surface; Receptors, Leptin; Retinal Neovascularization; Retinal Vessels; RNA, Messenger; STAT3 Transcription Factor; Trans-Activators; Up-Regulation; Vascular Endothelial Growth Factor A

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. Recently, leptin was found to be an angiogenic factor, and its vitreous levels are associated with angiogenic eye diseases such as proliferative diabetic retinopathy. However, the molecular mechanism for leptin-elicited angiogenesis remains to be elucidated. Pigment epithelium-derived factor (PEDF) has been shown to be the most potent natural inhibitor of angiogenesis in the mammalian eye, and its levels in the vitreous were decreased in angiogenic eye diseases. In this study, we investigated whether and how PEDF could inhibit the leptin-induced DNA synthesis in microvascular endothelial cells (EC), a key step of angiogenesis. Leptin significantly increased intracellular reactive oxygen species (ROS) generation in microvascular EC. PEDF was found to inhibit the leptin-induced ROS generation in EC. An anti-oxidant, N-acetylcysteine, or PEDF completely prevented the leptin-induced upregulation of vascular endothelial growth factor (VEGF) mRNA levels as well as any increase in DNA synthesis in microvascular EC. Polyclonal antibodies against human VEGF were also found to completely inhibit DNA synthesis in leptin-exposed EC. The present study suggests that leptin could elicit angiogenesis through autocrine VEGF production via intracellular ROS generation. PEDF may block the angiogenic effects of leptin through its anti-oxidative properties.

Topics: Acetylcysteine; Animals; Antioxidants; Brain; Cattle; DNA; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Eye Diseases; Eye Proteins; Gene Expression Regulation; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Microcirculation; Neovascularization, Pathologic; Nerve Growth Factors; Proteins; Reactive Oxygen Species; Receptors, Leptin; Receptors, Vascular Endothelial Growth Factor; Retinal Neovascularization; Retinal Vessels; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serpins; Thymidine; Time Factors; Vascular Endothelial Growth Factor A