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The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice
PURPOSE: Loss of retinal capillary endothelial cells and pericytes through apoptosis is an early event in diabetic retinopathy (DR). Inflammatory pathways play a role in early DR, yet the biochemical mechanisms are poorly understood. In this study, we investigated the role of indoleamine 2,3-dioxyge...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Association for Research in Vision and Ophthalmology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908388/ https://www.ncbi.nlm.nih.gov/pubmed/29677366 http://dx.doi.org/10.1167/iovs.17-22702 |
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author | Nahomi, Rooban B. Sampathkumar, Sruthi Myers, Angela M. Elghazi, Lynda Smith, Dawn G. Tang, Jie Lee, C. Allen Kern, Timothy S. Nagaraj, Ram H. Fort, Patrice E. |
author_facet | Nahomi, Rooban B. Sampathkumar, Sruthi Myers, Angela M. Elghazi, Lynda Smith, Dawn G. Tang, Jie Lee, C. Allen Kern, Timothy S. Nagaraj, Ram H. Fort, Patrice E. |
author_sort | Nahomi, Rooban B. |
collection | PubMed |
description | PURPOSE: Loss of retinal capillary endothelial cells and pericytes through apoptosis is an early event in diabetic retinopathy (DR). Inflammatory pathways play a role in early DR, yet the biochemical mechanisms are poorly understood. In this study, we investigated the role of indoleamine 2,3-dioxygenase (IDO), an inflammatory cytokine-inducible enzyme, on retinal endothelial apoptosis and capillary degeneration in the diabetic retina. METHODS: IDO was detected in human and mouse retinas by immunohistochemistry or Western blotting. Interferon-γ (IFN-γ) levels were measured by ELISA. IDO levels were measured in human retinal capillary endothelial cells (HREC) cultured in the presence of IFN-γ ± 25 mM D-glucose. Reactive oxygen species (ROS) were measured using CM-H(2)DCFDA dye and apoptosis was measured by cleaved caspase-3. The role of IDO in DR was determined in IDO knockout (IDO(−/−)) mice with streptozotocin-induced diabetes. RESULTS: The IDO and IFN-γ levels were higher in human diabetic retinas with retinopathy relative to nondiabetic retinas. Immunohistochemical data showed that IDO is present in capillary endothelial cells. IFN-γ upregulated the IDO and ROS levels in HREC. The blockade of either IDO or kynurenine monooxygenase led to inhibition of ROS in HREC. Apoptosis through this pathway was inhibited by an ROS scavenger, TEMPOL. Capillary degeneration was significantly reduced in diabetic IDO(−/−) mice compared to diabetic wild-type mice. CONCLUSIONS: The results suggest that the kynurenine pathway plays an important role in the inflammatory damage in the diabetic retina and could be a new therapeutic target for the treatment of DR. |
format | Online Article Text |
id | pubmed-5908388 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Association for Research in Vision and Ophthalmology |
record_format | MEDLINE/PubMed |
spelling | pubmed-59083882018-04-20 The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice Nahomi, Rooban B. Sampathkumar, Sruthi Myers, Angela M. Elghazi, Lynda Smith, Dawn G. Tang, Jie Lee, C. Allen Kern, Timothy S. Nagaraj, Ram H. Fort, Patrice E. Invest Ophthalmol Vis Sci Retina PURPOSE: Loss of retinal capillary endothelial cells and pericytes through apoptosis is an early event in diabetic retinopathy (DR). Inflammatory pathways play a role in early DR, yet the biochemical mechanisms are poorly understood. In this study, we investigated the role of indoleamine 2,3-dioxygenase (IDO), an inflammatory cytokine-inducible enzyme, on retinal endothelial apoptosis and capillary degeneration in the diabetic retina. METHODS: IDO was detected in human and mouse retinas by immunohistochemistry or Western blotting. Interferon-γ (IFN-γ) levels were measured by ELISA. IDO levels were measured in human retinal capillary endothelial cells (HREC) cultured in the presence of IFN-γ ± 25 mM D-glucose. Reactive oxygen species (ROS) were measured using CM-H(2)DCFDA dye and apoptosis was measured by cleaved caspase-3. The role of IDO in DR was determined in IDO knockout (IDO(−/−)) mice with streptozotocin-induced diabetes. RESULTS: The IDO and IFN-γ levels were higher in human diabetic retinas with retinopathy relative to nondiabetic retinas. Immunohistochemical data showed that IDO is present in capillary endothelial cells. IFN-γ upregulated the IDO and ROS levels in HREC. The blockade of either IDO or kynurenine monooxygenase led to inhibition of ROS in HREC. Apoptosis through this pathway was inhibited by an ROS scavenger, TEMPOL. Capillary degeneration was significantly reduced in diabetic IDO(−/−) mice compared to diabetic wild-type mice. CONCLUSIONS: The results suggest that the kynurenine pathway plays an important role in the inflammatory damage in the diabetic retina and could be a new therapeutic target for the treatment of DR. The Association for Research in Vision and Ophthalmology 2018-04 /pmc/articles/PMC5908388/ /pubmed/29677366 http://dx.doi.org/10.1167/iovs.17-22702 Text en Copyright 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. |
spellingShingle | Retina Nahomi, Rooban B. Sampathkumar, Sruthi Myers, Angela M. Elghazi, Lynda Smith, Dawn G. Tang, Jie Lee, C. Allen Kern, Timothy S. Nagaraj, Ram H. Fort, Patrice E. The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice |
title | The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice |
title_full | The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice |
title_fullStr | The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice |
title_full_unstemmed | The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice |
title_short | The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice |
title_sort | absence of indoleamine 2,3-dioxygenase inhibits retinal capillary degeneration in diabetic mice |
topic | Retina |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908388/ https://www.ncbi.nlm.nih.gov/pubmed/29677366 http://dx.doi.org/10.1167/iovs.17-22702 |
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