June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Lipocalin-2 homodimer variant: Role in dry age-related macular degeneration
Author Affiliations & Notes
  • Urvi Gupta
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Sayan Ghosh
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • PENG SHANG
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Haitao Liu
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Anastasiia Strizhakova
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Stacey L Hose
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • J. Samuel Zigler
    Ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States
  • Debasish Sinha
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Urvi Gupta None; Sayan Ghosh None; PENG SHANG None; Haitao Liu None; Anastasiia Strizhakova None; Stacey Hose None; J. Zigler None; Debasish Sinha None
  • Footnotes
    Support  This work is supported by NIH 1R01EY031594-01A1 (DS), the Jennifer Salvitti Davis, M.D. Chair Professorship in Ophthalmology (DS), start-up funds to DS from Ophthalmology, University of Pittsburgh, and Research to Prevent Blindness (Ophthalmology, UPMC).
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 4602 – F0394. doi:
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    • Get Citation

      Urvi Gupta, Sayan Ghosh, PENG SHANG, Haitao Liu, Anastasiia Strizhakova, Stacey L Hose, J. Samuel Zigler, Debasish Sinha; Lipocalin-2 homodimer variant: Role in dry age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2022;63(7):4602 – F0394.

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

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Abstract

Purpose : Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. We have shown that a pro-inflammatory adipokine, Lipocalin-2 (LCN-2), is upregulated in retinal pigment epithelium (RPE) cells in both a mouse model with a dry AMD-like phenotype and in early/dry human AMD donor samples, but only after chronic inflammation has been established. Many elegant studies have shown that LCN-2 exists as either a monomer or a homodimer variant. While the monomer is a potent iron chelator and has anti-microbial effects, the homodimer variant, which has a longer half-life, is unable to chelate iron and has been linked to the onset of several diseases. However, it is not known whether the homodimer variant is also upregulated in AMD nor if it is associated with disease progression. In this study, we evaluated the level of LCN-2 homodimer in AMD and investigated its possible role in inducing retinal degeneration.

Methods : Western blotting (WB) was performed on the RPE cell lysates under reducing and non-reducing conditions to evaluate the levels of the LCN-2 homodimer and monomer variants in our mouse model and human dry AMD donor samples. The levels of the LCN-2 variants were evaluated in spent medium from WT RPE explants overexpressing LCN-2 (RSM-LCN-2). To determine if the homodimer variant can induce retinal degeneration, NOD-SCID mice were injected with RSM-LCN-2, and effects on retinal structure (SD-OCT) and function (electroretinography) were assessed.

Results : WB analysis revealed an increased LCN-2 homodimer:monomer ratio in the RPE lysates from our mouse model and human AMD donors. The presence of the homodimer was confirmed by WB under reducing and non-reducing conditions. RSM-LCN-2 also showed elevated levels of the homodimer variant. Sub-retinal injection of RSM-LCN-2 in NOD-SCID mice, induced significant alterations in retinal structure and function.

Conclusions : Our data suggests that LCN-2 homodimer is the pathogenic form of the adipokine and is involved in AMD pathogenesis. Further, targeting/neutralizing the homodimer variant could be helpful in delaying the onset of retinal degeneration as seen in dry AMD, a multifactorial disease for which there are no treatment options at the present time.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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