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PPARδ Inhibits Hyperglycemia-Triggered Senescence of Retinal Pigment Epithelial Cells by Upregulating SIRT1
Emerging evidence shows that peroxisome proliferator-activated receptor delta (PPARδ) plays a pivotal role in cellular aging. However, its function in retinal disease processes such as hyperglycemia-associated diabetic retinopathy is unclear. Here, we demonstrate that PPARδ inhibits premature senesc...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9219651/ https://www.ncbi.nlm.nih.gov/pubmed/35740104 http://dx.doi.org/10.3390/antiox11061207 |
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author | Lee, Eun Ji Won, Jun Pil Lee, Hyuk Gyoon Kim, Eunsu Hur, Jinwoo Lee, Won Jin Hwang, Jung Seok Seo, Han Geuk |
author_facet | Lee, Eun Ji Won, Jun Pil Lee, Hyuk Gyoon Kim, Eunsu Hur, Jinwoo Lee, Won Jin Hwang, Jung Seok Seo, Han Geuk |
author_sort | Lee, Eun Ji |
collection | PubMed |
description | Emerging evidence shows that peroxisome proliferator-activated receptor delta (PPARδ) plays a pivotal role in cellular aging. However, its function in retinal disease processes such as hyperglycemia-associated diabetic retinopathy is unclear. Here, we demonstrate that PPARδ inhibits premature senescence of retinal pigment epithelial (RPE) cells induced by high glucose (HG) through SIRT1 upregulation. A specific ligand GW501516-activation of PPARδ suppressed premature senescence and production of reactive oxygen species induced by HG in ARPE-19 cells, a spontaneously arising human RPE cell line. These effects were accompanied by the regulation of the premature senescence-associated genes p53, p21, and SMP-30. Furthermore, GW501516-activated PPARδ almost completely abolished the effects of HG treatment on the formation of phosphorylated H2A histone family member X (γ-H2A.X) foci, a molecular marker of aging. These inhibitory effects of GW501516 were significantly reversed in ARPE-19 cells stably expressing small hairpin RNA targeting PPARδ. Notably, GW501516 significantly increased the mRNA and protein levels of SIRT1, indicating that GW501516-activated PPARδ exerted its beneficial effects through SIRT1. In addition, GW501516 restored HG-suppressed SIRT1 expression, corroborating the role of SIRT1 in the anti-senescence function of PPARδ. The effects of PPARδ on HG-induced premature senescence and the expression of the senescence-associated genes p53, p21, and SMP-30 were mimicked by the SIRT1 activator resveratrol, but blocked by the SIRT1 inhibitor sirtinol. Collectively, these results indicate that GW501516-activated PPARδ inhibits HG-triggered premature senescence of RPE cells by modulating SIRT1 signaling. |
format | Online Article Text |
id | pubmed-9219651 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92196512022-06-24 PPARδ Inhibits Hyperglycemia-Triggered Senescence of Retinal Pigment Epithelial Cells by Upregulating SIRT1 Lee, Eun Ji Won, Jun Pil Lee, Hyuk Gyoon Kim, Eunsu Hur, Jinwoo Lee, Won Jin Hwang, Jung Seok Seo, Han Geuk Antioxidants (Basel) Article Emerging evidence shows that peroxisome proliferator-activated receptor delta (PPARδ) plays a pivotal role in cellular aging. However, its function in retinal disease processes such as hyperglycemia-associated diabetic retinopathy is unclear. Here, we demonstrate that PPARδ inhibits premature senescence of retinal pigment epithelial (RPE) cells induced by high glucose (HG) through SIRT1 upregulation. A specific ligand GW501516-activation of PPARδ suppressed premature senescence and production of reactive oxygen species induced by HG in ARPE-19 cells, a spontaneously arising human RPE cell line. These effects were accompanied by the regulation of the premature senescence-associated genes p53, p21, and SMP-30. Furthermore, GW501516-activated PPARδ almost completely abolished the effects of HG treatment on the formation of phosphorylated H2A histone family member X (γ-H2A.X) foci, a molecular marker of aging. These inhibitory effects of GW501516 were significantly reversed in ARPE-19 cells stably expressing small hairpin RNA targeting PPARδ. Notably, GW501516 significantly increased the mRNA and protein levels of SIRT1, indicating that GW501516-activated PPARδ exerted its beneficial effects through SIRT1. In addition, GW501516 restored HG-suppressed SIRT1 expression, corroborating the role of SIRT1 in the anti-senescence function of PPARδ. The effects of PPARδ on HG-induced premature senescence and the expression of the senescence-associated genes p53, p21, and SMP-30 were mimicked by the SIRT1 activator resveratrol, but blocked by the SIRT1 inhibitor sirtinol. Collectively, these results indicate that GW501516-activated PPARδ inhibits HG-triggered premature senescence of RPE cells by modulating SIRT1 signaling. MDPI 2022-06-20 /pmc/articles/PMC9219651/ /pubmed/35740104 http://dx.doi.org/10.3390/antiox11061207 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lee, Eun Ji Won, Jun Pil Lee, Hyuk Gyoon Kim, Eunsu Hur, Jinwoo Lee, Won Jin Hwang, Jung Seok Seo, Han Geuk PPARδ Inhibits Hyperglycemia-Triggered Senescence of Retinal Pigment Epithelial Cells by Upregulating SIRT1 |
title | PPARδ Inhibits Hyperglycemia-Triggered Senescence of Retinal Pigment Epithelial Cells by Upregulating SIRT1 |
title_full | PPARδ Inhibits Hyperglycemia-Triggered Senescence of Retinal Pigment Epithelial Cells by Upregulating SIRT1 |
title_fullStr | PPARδ Inhibits Hyperglycemia-Triggered Senescence of Retinal Pigment Epithelial Cells by Upregulating SIRT1 |
title_full_unstemmed | PPARδ Inhibits Hyperglycemia-Triggered Senescence of Retinal Pigment Epithelial Cells by Upregulating SIRT1 |
title_short | PPARδ Inhibits Hyperglycemia-Triggered Senescence of Retinal Pigment Epithelial Cells by Upregulating SIRT1 |
title_sort | pparδ inhibits hyperglycemia-triggered senescence of retinal pigment epithelial cells by upregulating sirt1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9219651/ https://www.ncbi.nlm.nih.gov/pubmed/35740104 http://dx.doi.org/10.3390/antiox11061207 |
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