The lack of homology domain and leucine rich repeat protein phosphatase 2 ameliorates visual impairment in rats with diabetic retinopathy through regulation of the AKT-GSK-3β-Nrf2 signal cascade
Copyright © 2023 Elsevier Inc. All rights reserved..
Pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2) is an emerging player in diverse disorders. Our previous findings have documented that reducing PHLPP2 levels in cultured retinal ganglion cells protects against cellular damage caused by high glucose, indicating a possible link between PHLPP2 and diabetic retinopathy (DR). The present work was dedicated to the investigation of PHLPP2 in DR through in vivo experiments with rat models induced by intraperitoneal injection of streptozotocin. Compared to normal rats, the retinas of rats with DR exhibited a notable increase in the level of PHLPP2. The reduction of PHLPP2 levels in the retina was achieved by the intravitreal administration of adeno-associated viruses expressing specific shRNA targeting PHLPP2. Decreasing the expression of PHLPP2 ameliorated visual function impairment and improved the pathological changes of retina in DR rats. Moreover, decreasing the expression of PHLPP2 repressed the apoptosis, oxidative stress and proinflammatory response in the retinas of rats with DR. Reduction of PHLPP2 levels led to an increase in the levels of phosphorylated AKT and glycogen synthase kinase-3β (GSK-3β). Decreasing the expression of PHLPP2 resulted in increased activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which was reversed by suppressing AKT. Notably, the protective effect of reducing PHLPP2 on DR was eliminated when Nrf2 was restrained. These observations show that the down-regulation of PHLPP2 has protective effects on DR by preserving the structure and function of the retina by regulating the AKT-GSK-3β-Nrf2 signal cascade. Therefore, targeting PHLPP2 may hold promise in the treatment of DR.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:482 |
|---|---|
| Enthalten in: |
Toxicology and applied pharmacology - 482(2024) vom: 01. Jan., Seite 116766 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Chen, Li [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 17.01.2024 Date Revised 23.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.taap.2023.116766 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM364870672 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM364870672 | ||
| 003 | DE-627 | ||
| 005 | 20240229143849.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.taap.2023.116766 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1303.xml |
| 035 | |a (DE-627)NLM364870672 | ||
| 035 | |a (NLM)37995808 | ||
| 035 | |a (PII)S0041-008X(23)00405-2 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Chen, Li |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The lack of homology domain and leucine rich repeat protein phosphatase 2 ameliorates visual impairment in rats with diabetic retinopathy through regulation of the AKT-GSK-3β-Nrf2 signal cascade |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 17.01.2024 | ||
| 500 | |a Date Revised 23.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a Pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2) is an emerging player in diverse disorders. Our previous findings have documented that reducing PHLPP2 levels in cultured retinal ganglion cells protects against cellular damage caused by high glucose, indicating a possible link between PHLPP2 and diabetic retinopathy (DR). The present work was dedicated to the investigation of PHLPP2 in DR through in vivo experiments with rat models induced by intraperitoneal injection of streptozotocin. Compared to normal rats, the retinas of rats with DR exhibited a notable increase in the level of PHLPP2. The reduction of PHLPP2 levels in the retina was achieved by the intravitreal administration of adeno-associated viruses expressing specific shRNA targeting PHLPP2. Decreasing the expression of PHLPP2 ameliorated visual function impairment and improved the pathological changes of retina in DR rats. Moreover, decreasing the expression of PHLPP2 repressed the apoptosis, oxidative stress and proinflammatory response in the retinas of rats with DR. Reduction of PHLPP2 levels led to an increase in the levels of phosphorylated AKT and glycogen synthase kinase-3β (GSK-3β). Decreasing the expression of PHLPP2 resulted in increased activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which was reversed by suppressing AKT. Notably, the protective effect of reducing PHLPP2 on DR was eliminated when Nrf2 was restrained. These observations show that the down-regulation of PHLPP2 has protective effects on DR by preserving the structure and function of the retina by regulating the AKT-GSK-3β-Nrf2 signal cascade. Therefore, targeting PHLPP2 may hold promise in the treatment of DR | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AKT | |
| 650 | 4 | |a Diabetic Retinopathy | |
| 650 | 4 | |a Nrf2 | |
| 650 | 4 | |a PHLPP2 | |
| 650 | 4 | |a Retina | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Protein Phosphatase 2 |2 NLM | |
| 650 | 7 | |a EC 3.1.3.16 |2 NLM | |
| 650 | 7 | |a Glycogen Synthase Kinase 3 beta |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a NF-E2-Related Factor 2 |2 NLM | |
| 650 | 7 | |a Leucine-Rich Repeat Proteins |2 NLM | |
| 700 | 1 | |a Qi, En |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xuan |e verfasserin |4 aut | |
| 700 | 1 | |a Cui, Lijun |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Xiaojuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Yaguang |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Toxicology and applied pharmacology |d 1959 |g 482(2024) vom: 01. Jan., Seite 116766 |w (DE-627)NLM000010979 |x 1096-0333 |7 nnns |
| 773 | 1 | 8 | |g volume:482 |g year:2024 |g day:01 |g month:01 |g pages:116766 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.taap.2023.116766 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 482 |j 2024 |b 01 |c 01 |h 116766 | ||