title: Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism.
abstract: Serum retinol-binding protein 4 (RBP4) is the sole specific transport protein for retinol in the blood, but it is also an adipokine with retinol-independent, proinflammatory activity associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. Moreover, two separate studies reported that patients with proliferative diabetic retinopathy have increased serum RBP4 levels compared to patients with mild or no retinopathy, yet the effect of increased levels of RBP4 on the retina has not been studied. Here we show that transgenic mice overexpressing RBP4 (RBP4-Tg mice) develop progressive retinal degeneration, characterized by photoreceptor ribbon synapse deficiency and subsequent bipolar cell loss. Ocular retinoid and bisretinoid levels are normal in RBP4-Tg mice, demonstrating that a retinoid-independent mechanism underlies retinal degeneration. Increased expression of pro-interleukin-18 (pro-IL-18) mRNA and activated IL-18 protein and early-onset microglia activation in the retina suggest that retinal degeneration is driven by a proinflammatory mechanism. Neither chronic systemic metabolic disease nor other retinal insults are required for RBP4 elevation to promote retinal neurodegeneration, since RBP4-Tg mice do not have coincident retinal vascular pathology, obesity, dyslipidemia, or hyperglycemia. These findings suggest that elevation of serum RBP4 levels could be a risk factor for retinal damage and vision loss in nondiabetic as well as diabetic patients.
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Du
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Otalora
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Martin
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Moiseyev
authors.affiliation: EyeCRO LLC, Oklahoma City, Oklahoma, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Vanlandingham
authors.affiliation: Department of Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Qilong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: EyeCRO LLC, Oklahoma City, Oklahoma, USA.
authors.forename: Rafal
authors.initials: R
authors.lastname: Farjo
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Yeganeh
authors.affiliation: EyeCRO LLC, Oklahoma City, Oklahoma, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Quiambao
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA Krysten-Farjo@ouhsc.edu.
authors.forename: Krysten M
authors.initials: KM
authors.lastname: Farjo
mesh_terms: D000375:Aging; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D020382:Interleukin-18 / Q000235:genetics; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D012162:Retinal Degeneration / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D012176:Retinoids / Q000032:analysis*; D054839:Retinol-Binding Proteins, Plasma / Q000032:analysis / Q000235:genetics*; D013569:Synapses / Q000235:genetics / Q000473:pathology; D015854:Up-Regulation
chemical_list: D020382:Interleukin-18; C502487:Rbp4 protein, mouse; D012176:Retinoids; D054839:Retinol-Binding Proteins, Plasma