September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
An AAV2 vector encoding prolactin reverses blood retinal barrier pathology when administered intravitreally to diabetic rats
Author Affiliations & Notes
  • Nundehui Diaz-Lezama
    Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico (UNAM), Queretaro, Queretaro, Mexico
  • Zhijian Wu
    Ocular Gene Therapy Laboratory, National Institute of Health , Bethesda, Maryland, United States
  • Elva Adan-Castro
    Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico (UNAM), Queretaro, Queretaro, Mexico
  • Bibiana Moreno-Carranza
    Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico (UNAM), Queretaro, Queretaro, Mexico
  • Gonzalo Martinez de la Escalera
    Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico (UNAM), Queretaro, Queretaro, Mexico
  • Carmen Clapp
    Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico (UNAM), Queretaro, Queretaro, Mexico
  • Footnotes
    Commercial Relationships   Nundehui Diaz-Lezama, None; Zhijian Wu, None; Elva Adan-Castro, None; Bibiana Moreno-Carranza, None; Gonzalo Martinez de la Escalera, None; Carmen Clapp, None
  • Footnotes
    Support  National Council of Science and Technology of Mexico (CONACYT) grant 247164
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 758. doi:
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      Nundehui Diaz-Lezama, Zhijian Wu, Elva Adan-Castro, Bibiana Moreno-Carranza, Gonzalo Martinez de la Escalera, Carmen Clapp; An AAV2 vector encoding prolactin reverses blood retinal barrier pathology when administered intravitreally to diabetic rats. Invest. Ophthalmol. Vis. Sci. 2016;57(12):758.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Prolactin (PRL), the hormone essential for lactation, is converted by proteolytic cleavage to vasoinhibins, a family of PRL fragments that inhibit diabetes-induced blood retinal barrier breakdown (BRBB) by targeting both the inner (vascular endothelial cells) and outer (retinal pigment epithelium) components of the BRB (Garcia et al., JCI. 118:2291, 2008; Arredondo-Zamarripa et al., Front. Cell. Neurosci. 8:333, 2014). Because elevated PRL circulating levels upregulate retinal vasoinhibins (Arnold et al., Diabetes 59:3192, 2010), we reasoned that the intravitreal administration of an adeno-associated virus type 2 vector encoding PRL (AAV2 PRL) would reduce BRBB in diabetic rats by serving as a source of vasoinhibins.

Methods : The AAV2 PRL vector was injected intravitreally before or after inducing diabetes with streptozotocin (STZ) in rats. The ability of the vector to reduce BRBB was examined by the Evans blue method four or six weeks after STZ injection. AAV2 PRL transgene expression and the levels of endogenous vasoinhibins were compared between the retinas of diabetic rats and non-diabetic controls.

Results : The AAV2 PRL vector inhibited the diabetes-mediated increase in BRBB when injected after, but not before, diabetes was induced. Expression of the PRL transgene was higher in the retinas from diabetic rats. Also, vasoinhibin levels were higher in the retinas of diabetic rats compared to the non-diabetic controls.

Conclusions : We conclude that the AAV2 PRL vector inhibits BRBB by enhancing the intraocular generation of vasoinhibins. This effect depends on the conditions of the diabetic rat retina, which include an elevated transgene expression due to increased cell entry by the vector (Diaz-Lezama et al., Lab. Invest., doi 10.1038/labinvest.2015.135) and, very likely, the enhanced activity of the cleaving enzymes that convert PRL to vasoinhibins. Experiments addressing this last possibility are underway.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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