Poster Topical Area: Maternal, Perinatal and Pediatric Nutrition

Location: Hall D

Poster Board Number: 307

P13-049 - Adiponectin modulates photoreceptor metabolism to prevent hyperglycemic retinopathy of prematurity

Sunday, Jun 10
8:00 AM – 6:00 PM

Objective: Hyperglycemia is a novel risk factor for retinopathy of prematurity (ROP) but its impact is understudied. ROP is a leading cause of blindness in children with early vessel loss followed by neovascularization. We investigated if hyperglycemia inhibited retinal neurovascular development in a newly established mouse model, and if adiponectin (APN) protected against hyperglycemic ROP.


Methods:
To induce hyperglycemia, C57BL/6J (WT) and APN-deficient (Apn-/-) mouse neonatal pups were treated with continuous lose dose streptozotocin (STZ) for 9 days. Blood glucose, serum insulin levels were measured (n=4-7). Retinal vascular network (n=17-27) and retinal function (n=7-12) were examined. Retinal key metabolic enzyme levels were measured by quantitative proteomics (n=6). Localization of APN receptors was examined by qPCR in laser-captured-microdissected retinal neurons (n=3). Oxygen consumption rate in 661W photoreceptor cells and hyperglycemic retinas was measured by Seahorse analysis (n=9). AAV2-RK-shPdgfb was used for photoreceptor-specific knockdown of PDGFB.


Results:
In STZ-treated WT mice, higher blood glucose and lower serum insulin levels were found. Hyperglycemia delayed retinal vascular growth and decreased retinal function. APN deficiency further inhibited retinal vessel growth. APN administration in hyperglycemic WT mice restored retinal vessel growth and retinal function (particularly cones). APN receptor AdipoR1 was dominantly expressed in photoreceptors. APN deficiency reduced retinal metabolic enzyme levels. Activation of the APN pathway increased oxygen consumption rate (mitochondrial activity) of hyperglycemic retinas and 661W. Blockade of mitochondrial respiration abolished Pdgfb induction by activating the APN pathway in 661W. APN deficiency reduced Pdgfb expression in photoreceptors and photoreceptor-knockdown of Pdgfb inhibited retinal vessel growth.


Conclusions:
APN modulates photoreceptor metabolism to prevent hyperglycemia-associated retinal abnormalities at early stage. Supplementation of recombinant APN in parental nutrition may suppress ROP in premature infants.




Funding Source:

Funding: The work is supported by NIH EY024864, EY017017, BCH IDDRC (1U54HD090255), Lowy Medical Research Institute, European Commission FP7 project 305485 PREVENT-ROP (LEHS); The Swedish Research Council (DNR# 2011-2432) and Gothenburg County Council (ALFGBG-426531) long-term support by De Blindas Vänner and Kronprinsessan Margaretas Arbetsnämnd för synskadade (AH); project 305485 PREVENT-ROP (VINNOVA 2009-01152) from the European Commission FP7 (CAL); NIH P30AG050911 and the Harold Hamm Diabetes Center at the University of Oklahoma (MK). Knights Templar Eye Foundation (#76293) and Blind Children's Center (#89282) (ZF); the German Research Foundation (DFG), Li2650/1-1 (RL). Knights Templar Eye Foundation (CHL); Boston Children's Hospital OFD/BTREC/CTREC Faculty Career Development Grant (YS).

CoAuthors: Chatarina Löfqvist – University of Gothenburg; Raffael Liegl – Boston Children's Hospital / Havard Medical School; Zhongxiao Wang – Boston Children’s Hospital / Harvard Medical School; Ye Sun – Boston Children’s Hospital / Harvard Medical School; Chi-Hsiu Liu – Boston Children’s Hospital / Harvard Medical School; Rubi Duran – Boston Children’s Hospital / Harvard Medical School; Alexander Poblete – Boston Children’s Hospital / Harvard Medical School; Steve Cho – Boston Children’s Hospital / Harvard Medical School; James Akula – Boston Children’s Hospital / Harvard Medical School; Mike Kinter – University of Oklahoma Health Sciences Center; Saswata Talukdar – Merck; Ann Hellström – University of Gothenburg; Lois Smith – Boston Children’s Hospital / Harvard Medical School

Zhongjie Fu

Instructor
Harvard Medical School / Boston Children's Hospital
Boston, Massachusetts