title: Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1α-VEGF pathway inhibition.
abstract: A new diabetic mouse strain, the Akita.PlGF knockout ((-/-)), was generated to study the role of placental growth factor (PlGF) in the pathogenesis of diabetic retinopathy (DR). PlGF deletion did not affect blood glucose but reduced the body weight of Akita.PlGF(-/-) mice. Diabetes-induced retinal cell death, capillary degeneration, pericyte loss, and blood-retinal barrier breakdown were prevented in these mice. Protein expression of PlGF was upregulated by diabetes, particularly in vascular cells. Diabetes-induced degradation of ZO-1 and VE-cadherin was reversed due to PlGF deficiency; their expression was correlated with that of sonic hedgehog and angiopoietin-1. PlGF deletion in Akita mice resulted in an increased Akt phosphorylation. Diabetes-activated hypoxia-inducible factor (HIF)1α-vascular endothelial growth factor (VEGF) pathway, including expression of HIF1α, VEGF, VEGFR1-3, and the extent of phospho (p)-VEGFR1, p-VEGFR2, and p-endothelial nitric oxide synthase, was inhibited in the retinas of diabetic PlGF(-/-) mice. However, expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, CD11b, and CD18 was not inhibited by PlGF deletion, nor was retinal leukostasis. These results suggest that PlGF is critical for the development of DR, and its genetic deletion protects the retina from diabetic damage. Protective mechanisms are associated with Akt activation and HIF1α-VEGF pathway inhibition, but independent of retinal leukostasis in the retinas of diabetic PlGF(-/-) mice.
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD hhuang27@jhmi.edu.
authors.forename: Hu
authors.initials: H
authors.lastname: Huang
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD Guangxi Tumor Hospital and Institute, Nanning, Guangxi, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: He
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Da'Kuawn
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD Aier Eye Hospital, Changsha, Hunan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD China Japan Union Hospital, Changchun, Jilin, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Lutty
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Elia J
authors.initials: EJ
authors.lastname: Duh
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Semba
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D001786:Blood Glucose; D015820:Cadherins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D051057:Proto-Oncogene Proteins c-akt; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D000099152:Cadherin 5; C497443:Hif1a protein, mouse; C000608037:Pgf protein, mouse; C569043:Tjp1 protein, mouse; C467480:vascular endothelial growth factor A, mouse