The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice
Inflammation has been implicated in a variety of retinal diseases. The immunoproteasome plays a critical role in controlling inflammatory responses, but whether activation of immunoproteasome contributes to angiotensin II (Ang II)-induced retinopathy remains unclear. Hypertensive retinopathy (HR) wa...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2018-06-01
|
Series: | Redox Biology |
Online Access: | http://www.sciencedirect.com/science/article/pii/S221323171830123X |
id |
doaj-18d16b7bca6b493886988fc30af84df7 |
---|---|
record_format |
Article |
spelling |
doaj-18d16b7bca6b493886988fc30af84df72020-11-25T03:25:12ZengElsevierRedox Biology2213-23172018-06-0116129138The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in miceShuai Wang0Jing Li1Jie Bai2Jing-Min Li3Yi-Lin Che4Qiu-Yue Lin5Yun-Long Zhang6Hui-Hua Li7Department of Ophthalmology, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China; School of Public Health, Dalian Medical University, Dalian 116004, ChinaDepartment of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 11600, ChinaSchool of Public Health, Dalian Medical University, Dalian 116004, ChinaDepartment of Ophthalmology, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, ChinaDepartment of Radiotherapy Oncology, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, ChinaDepartment of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 11600, ChinaDepartment of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 11600, ChinaDepartment of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 11600, China; School of Public Health, Dalian Medical University, Dalian 116004, China; Corresponding author at: Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.Inflammation has been implicated in a variety of retinal diseases. The immunoproteasome plays a critical role in controlling inflammatory responses, but whether activation of immunoproteasome contributes to angiotensin II (Ang II)-induced retinopathy remains unclear. Hypertensive retinopathy (HR) was induced by infusion of Ang II (3000 ng/kg/min) in wild-type (WT) and immunoproteasome subunit LMP10 knockout (KO) mice for 3 weeks. Changes in retinal morphology, vascular permeability, superoxide production and inflammation were examined by pathological staining. Our results showed that immunoproteasome subunit LMP10 expression and its trypsin-like activity were significantly upregulated in the retinas and serum of Ang II-infused mice and in the serum from patients with hypertensive retinopathy. Moreover, Ang II-infused WT mice showed an increase in the central retinal thickness, vascular permeability, reactive oxygen species (ROS) production and inflammation compared with saline controls, and these effects were significantly attenuated in LMP10 KO mice, but were aggravated in mice intravitreally injected with rAAV2-LMP10. Interestingly, administration of IKKβ specific inhibitor IMD-0354 remarkably blocked an Ang II-induced increase in vascular permeability, oxidative stress and inflammation during retinopathy. Mechanistically, Ang II-induced upregulation of LMP10 promoted PTEN degradation and activation of AKT/IKK signaling, which induced IkBα phosphorylation and subsequent degradation ultimately leading to activation of NF-kB target genes in retinopathy. Therefore, this study provided novel evidence demonstrating that LMP10 is a positive regulator of NF-kB signaling, which contributes to Ang II-induced retinopathy. Strategies for inhibiting LMP10 or IKKβ activity in the eye could serve as a novel therapeutic target for treating hypertensive retinopathy. Keywords: Angiotensin II, Retinopathy, Immunoproteasome LMP10, Vascular permeability, Oxidative stress, Inflammationhttp://www.sciencedirect.com/science/article/pii/S221323171830123X |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shuai Wang Jing Li Jie Bai Jing-Min Li Yi-Lin Che Qiu-Yue Lin Yun-Long Zhang Hui-Hua Li |
spellingShingle |
Shuai Wang Jing Li Jie Bai Jing-Min Li Yi-Lin Che Qiu-Yue Lin Yun-Long Zhang Hui-Hua Li The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice Redox Biology |
author_facet |
Shuai Wang Jing Li Jie Bai Jing-Min Li Yi-Lin Che Qiu-Yue Lin Yun-Long Zhang Hui-Hua Li |
author_sort |
Shuai Wang |
title |
The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice |
title_short |
The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice |
title_full |
The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice |
title_fullStr |
The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice |
title_full_unstemmed |
The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice |
title_sort |
immunoproteasome subunit lmp10 mediates angiotensin ii-induced retinopathy in mice |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2018-06-01 |
description |
Inflammation has been implicated in a variety of retinal diseases. The immunoproteasome plays a critical role in controlling inflammatory responses, but whether activation of immunoproteasome contributes to angiotensin II (Ang II)-induced retinopathy remains unclear. Hypertensive retinopathy (HR) was induced by infusion of Ang II (3000 ng/kg/min) in wild-type (WT) and immunoproteasome subunit LMP10 knockout (KO) mice for 3 weeks. Changes in retinal morphology, vascular permeability, superoxide production and inflammation were examined by pathological staining. Our results showed that immunoproteasome subunit LMP10 expression and its trypsin-like activity were significantly upregulated in the retinas and serum of Ang II-infused mice and in the serum from patients with hypertensive retinopathy. Moreover, Ang II-infused WT mice showed an increase in the central retinal thickness, vascular permeability, reactive oxygen species (ROS) production and inflammation compared with saline controls, and these effects were significantly attenuated in LMP10 KO mice, but were aggravated in mice intravitreally injected with rAAV2-LMP10. Interestingly, administration of IKKβ specific inhibitor IMD-0354 remarkably blocked an Ang II-induced increase in vascular permeability, oxidative stress and inflammation during retinopathy. Mechanistically, Ang II-induced upregulation of LMP10 promoted PTEN degradation and activation of AKT/IKK signaling, which induced IkBα phosphorylation and subsequent degradation ultimately leading to activation of NF-kB target genes in retinopathy. Therefore, this study provided novel evidence demonstrating that LMP10 is a positive regulator of NF-kB signaling, which contributes to Ang II-induced retinopathy. Strategies for inhibiting LMP10 or IKKβ activity in the eye could serve as a novel therapeutic target for treating hypertensive retinopathy. Keywords: Angiotensin II, Retinopathy, Immunoproteasome LMP10, Vascular permeability, Oxidative stress, Inflammation |
url |
http://www.sciencedirect.com/science/article/pii/S221323171830123X |
work_keys_str_mv |
AT shuaiwang theimmunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT jingli theimmunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT jiebai theimmunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT jingminli theimmunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT yilinche theimmunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT qiuyuelin theimmunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT yunlongzhang theimmunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT huihuali theimmunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT shuaiwang immunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT jingli immunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT jiebai immunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT jingminli immunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT yilinche immunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT qiuyuelin immunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT yunlongzhang immunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice AT huihuali immunoproteasomesubunitlmp10mediatesangiotensiniiinducedretinopathyinmice |
_version_ |
1724598291908263936 |