July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Targeting LXR using N,N-dimethyl-3ß-hydroxycholenamide (DMHCA) provides protection from development of diabetic retinopathy in db/db mice
Author Affiliations & Notes
  • Cristiano Pedrozo Vieira
    University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Ana Leda Figueiredo Longhini
    University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Sergio L Calzi
    University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Bright Asare-Bediako
    University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Mariana Dupont
    University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Julia V Busik
    Michigan state University, Michigan, United States
  • Maria B Grant
    University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Footnotes
    Commercial Relationships   Cristiano Pedrozo Vieira, None; Ana Leda Longhini, None; Sergio Calzi, None; Bright Asare-Bediako, None; Mariana Dupont, None; Julia Busik, None; Maria Grant, None
  • Footnotes
    Support  NH Grant EY025383
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2788. doi:https://doi.org/
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      Cristiano Pedrozo Vieira, Ana Leda Figueiredo Longhini, Sergio L Calzi, Bright Asare-Bediako, Mariana Dupont, Julia V Busik, Maria B Grant; Targeting LXR using N,N-dimethyl-3ß-hydroxycholenamide (DMHCA) provides protection from development of diabetic retinopathy in db/db mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2788. doi: https://doi.org/.

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

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Abstract

Purpose : LXR activation increases cholesterol removal through reverse cholesterol transport and suppresses inflammatory gene expression, thus controlling the immune response and subsequent development of inflammation. Both RCT and the metabolism of cholesterol are active in the retina. Diabetes is associated with systemic inflammation mediated largely by myeloidosis in the bone marrow (BM) which can contribute to the pathogenesis of diabetic retinopathy (DR). As DMHCA is an agonist for LXR, we sought to test whether progression of DR could be prevented using DMHCA and its impact generation of inflammatory cells by the bone marrow.

Methods : db/db mice were given DMHCA (8 mg/kg body weigh/day) in their chow or fed normal chow beginning at diabetes onset. Mice were euthanized and retinal tissue was collected. Retinal inflammation was assessed by quantitation of M1 and M2 macrophages, CD45+ cells. Retinal lipids were assessed by Mass Spectroscopy. Electroretinograms (ERG) were performed in both periods. The BM supernatant was analyzed for cytokines quantifications and BM progenitor cells were characterized by flow cytometry.

Results : db/db mice with 2 and 6 months of diabetes showed a significant reduction in the ERG scotopic response (76±20µV vs 229±50 in DMHCA db/db in 6 months), compared to controls (194±60µV).CD45+ cells within the retina were increased in db/db mice (55±7) and reduced in DMHCA-treated db/db mice (31±7). The % of M1 macrophages in the retina was decreased in DMHCA-treated db/db (79±2) mice compared to db/db (87±3) while the percentage of M2 macrophages showed increased in DMHCA cohort (17±2) in comparison with db/db (9±2). The ratio of total cholesterol/demosterol/lanosterol had increased in DMHCA-treated db/db mice (199±45) compared to db/db (65±12). Most interestingly, DMHCA-treated decreased the % of Granulocyte-macrophage progenitors (1.9±0.3 vs 2.8±0.6 db/db) and IL-1 beta (6±0.4 vs 10±2.4 db/db) and IL-3 (0.26±0.03 vs 0.6±0.03 db/db) levels in BM.

Conclusions : These findings support that LXR activation by DMHCA provides protective effects on the diabetic retina, by improving significantly the visual response and reducing inflammatory cell infiltration into the retina. In addition, DMHCA treatment resulted in beneficial changes the bone marrow as demonstrated by a decrease the production of inflammatory cells and cytokines.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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