title: The effects of pleiotrophin in proliferative diabetic retinopathy.
abstract: Pleiotrophin (PTN), a secreted, multifunctional cytokine, is involved in angiogenic, fibrotic and neurodegenerative diseases. However, little is known about its effects on diabetic retinopathy, a neurovascular disease. To investigate the role of PTN in proliferative diabetic retinopathy (PDR), PTN concentration in the vitreous was evaluated in PDR patients and non-diabetic controls. PTN expression was observed in epiretinal membranes from patients. PTN knockdown was performed using small interfering (si)RNA, and the effects on retinal pigment epithelium (RPE) cells and human umbilical vascular endothelia cells (HUVECs) were observed in vitro under hyperglycemic and hypoxic conditions. Cell attachment, proliferation, migration, tube formation, cell cycle, apoptosis, extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation, and VEGF levels were studied. The vitreous PTN concentration in PDR patients was higher than that in non-diabetic controls, and PTN was highly expressed in the fibrovascular membranes of PDR patients. Under hyperglycemic and hypoxic conditions, PTN knockdown reduced cell attachment, proliferation, migration, and tube formation and induced cell cycle arrest and apoptosis in vitro. Mechanically, PTN depletion decreased ERK 1/2 phosphorylation. Recombinant PTN up regulated the concentration of VEGF in vitro, which can be attenuated by the ERK 1/2 inhibitor. Taken together, our results implied that elevated PTN in PDR patients might participate in the critical processes of the development of PDR, most likely playing roles in angiogenesis and proliferation, possibly by activating the ERK 1/2 pathway and regulating VEGF secretion. These findings provide new insight into the roles of PTN in PDR and suggest that PTN may become a new target for therapeutic intervention in PDR.
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Chungting
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Enzhong
authors.initials: E
authors.lastname: Jin
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Song
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Yuou
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Lvzhen
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, 100044, China.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Zhao
mesh_terms: D000368:Aged; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion; D015687:Cell Hypoxia; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003930:Diabetic Retinopathy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D019773:Epiretinal Membrane / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D034622:RNA Interference; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014822:Vitreous Body / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D009414:Nerve Growth Factors; D042461:Vascular Endothelial Growth Factor A; C066845:pleiotrophin; D048052:Mitogen-Activated Protein Kinase 3