September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Helping retina to breathe by increasing fetal hemoglobin production in RPE: relevance to outer retinal preservation in hypoxic conditions characteristic of aging and diabetes
Author Affiliations & Notes
  • Pamela M Martin
    Biochemistry & Molecular Biology, Georgia Regents University, Augusta, Georgia, United States
    Ophthalmology and Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, United States
  • Wanwisa Promsote
    Biochemistry & Molecular Biology, Georgia Regents University, Augusta, Georgia, United States
  • Folami Lamoke Powell
    Biochemistry & Molecular Biology, Georgia Regents University, Augusta, Georgia, United States
  • Alan Saul
    Ophthalmology and Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, United States
  • Vadivel Ganapathy
    Cell Biology & Biochemistry, Texas Tech University Health Science Center, Lubbock, Texas, United States
  • Pamela M Martin
    Biochemistry & Molecular Biology, Georgia Regents University, Augusta, Georgia, United States
    Ophthalmology and Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, United States
  • Footnotes
    Commercial Relationships   Pamela Martin, Georgia Regents University (P); Wanwisa Promsote, None; Folami Powell, None; Alan Saul, None; Vadivel Ganapathy, Georgia Regents University (P); Pamela Martin, Georgia Regents University (P)
  • Footnotes
    Support  NIH Grant EY022704
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 242. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Pamela M Martin, Wanwisa Promsote, Folami Lamoke Powell, Alan Saul, Vadivel Ganapathy, Pamela M Martin; Helping retina to breathe by increasing fetal hemoglobin production in RPE: relevance to outer retinal preservation in hypoxic conditions characteristic of aging and diabetes. Invest. Ophthalmol. Vis. Sci. 2016;57(12):242.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : In normal adults, 97% of total red cell hemoglobin (Hb) is adult Hb (HbA). Elevated fetal Hb (HbF) levels post-infancy generally indicate underlying metabolic stress and tissue hypoxia. HbF binds oxygen with higher affinity than HbA; increased HbF production is regarded as a “rescue” attempt by the body to increase oxygen extraction and subsequent delivery to tissues under low oxygen conditions. Hb production by RPE brings new perspectives regarding the understanding of outer retinal oxygenation under normal conditions. In light of this discovery, the known high metabolic activity and consequent demand of photoreceptors for oxygen, here we evaluated whether HbF modulation confers benefit in retina under hypoxic conditions characteristic of aging and diabetes. Additionally, we investigated the underlying molecular mechanisms responsible.

Methods : Mice engineered to produce human Hb were used in this study: abnormal Hb (HbSS)-producing mice to study the effects of HbF augmentation on chronic, low-grade hypoxia that occurs in aging and, normal Hb (HbAA)-producing mice ± STZ, to examine its effects on diabetes-induced hypoxia. Animals were treated ± the HbF-inducer monomethylfumarate (MMF; 15 mg/ml in drinking water). Retinal health/function was monitored by ERG, OCT, and routine histologic, RNA and protein analyses. MMF-induced alterations in gene/protein expression were evaluated also in ARPE-19 cells cultured ± MMF (100 μM) under normal, hyperglycemic (25 mM glucose) or hypoxic (100 μM CoCl2 or 1% oxygen) conditions.

Results : Oral MMF-therapy increased γ-globin mRNA/HbF production systemically and in retina, reduced oxidative stress/inflammation, and preserved outer retinal morphology/function positively in chronically hypoxic retinas (HbSS and HbAA+STZ). MMF induced Nrf2 and downregulated Bcl11A, a repressor of γ-globin transcription and regulator of cell metabolism and senescence. siRNA studies demonstrated the effect on Bcl11A to be Nrf2-dependent.

Conclusions : This study exposes novel potential links between factor that govern globin gene switching, redox status, metabolism and senescence and suggests that HbF-inducing therapies might afford multiple levels of benefit in hypoxic retina.

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

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×