Leptin stimulates ischemia-induced retinal neovascularization: possible role of vascular endothelial growth factor expressed in retinal endothelial cells.
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.
Suganami
Eri
E
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Takagi
Hitoshi
H
Ohashi
Hirokazu
H
Suzuma
Kiyoshi
K
Suzuma
Izumi
I
Oh
Hideyasu
H
Watanabe
Daisuke
D
Ojima
Tomonari
T
Suganami
Takayoshi
T
Fujio
Yasushi
Y
Nakao
Kazuwa
K
Ogawa
Yoshihiro
Y
Yoshimura
Nagahisa
N
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression; D007511:Ischemia / Q000503:physiopathology*; D020738:Leptin / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010100:Oxygen / Q000494:pharmacology; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000378:metabolism; D054411:Receptors, Leptin; D015861:Retinal Neovascularization / Q000503:physiopathology*; D012171:Retinal Vessels / Q000187:drug effects / Q000502:physiology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D004268:DNA-Binding Proteins; D020738:Leptin; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; C515447:leptin receptor, mouse; D010100:Oxygen