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Inner retinal injury in experimental glaucoma is prevented upon AAV mediated Shp2 silencing in a caveolin dependent manner
- Source :
- Theranostics
- Publication Year :
- 2021
- Publisher :
- Ivyspring International Publisher, 2021.
-
Abstract
- SH2 domain containing tyrosine phosphatase 2 (Shp2; PTPN11) regulates several intracellular pathways downstream of multiple growth factor receptors. Our studies implicate that Shp2 interacts with Caveolin-1 (Cav-1) protein in retinal ganglion cells (RGCs) and negatively regulates BDNF/TrkB signaling. This study aimed to investigate the mechanisms underlying the protective effects of shp2 silencing in the RGCs in glaucomatous conditions. Methods: Shp2 was silenced in the Cav-1 deficient mice and the age matched wildtype littermates using adeno-associated viral (AAV) constructs. Shp2 expression modulation was performed in an acute and a chronic mouse model of experimental glaucoma. AAV2 expressing Shp2 eGFP-shRNA under a strong synthetic CAG promoter was administered intravitreally in the animals' eyes. The contralateral eye received AAV-eGFP-scramble-shRNA as control. Animals with Shp2 downregulation were subjected to either microbead injections or acute ocular hypertension experimental paradigm. Changes in inner retinal function were evaluated by measuring positive scotopic threshold response (pSTR) while structural and biochemical alterations were evaluated through H&E staining, western blotting and immunohistochemical analysis of the retinal tissues. Results: A greater loss of pSTR amplitudes was observed in the WT mice compared to Cav-1-/- retinas in both the models. Silencing of Shp2 phosphatase imparted protection against inner retinal function loss in chronic glaucoma model in WT mice. The functional rescue also translated to structural preservation of ganglion cell layer in the chronic glaucoma condition in WT mice which was not evident in Cav-1-/- mice retinas. Conclusions: This study indicates that protective effects of Shp2 ablation under chronic experimental glaucoma conditions are dependent on Cav-1 in the retina, suggesting in vivo interactions between the two proteins.
- Subjects :
- 0301 basic medicine
genetic structures
Caveolin 1
Medicine (miscellaneous)
Glaucoma
Apoptosis
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Tropomyosin receptor kinase B
chemistry.chemical_compound
Mice
0302 clinical medicine
TrkB
Genes, Reporter
Genes, Synthetic
Promoter Regions, Genetic
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Mice, Knockout
Membrane Glycoproteins
Chemistry
Integrin beta1
Dependovirus
Protein-Tyrosine Kinases
Cell biology
Up-Regulation
medicine.anatomical_structure
Gene Knockdown Techniques
Intravitreal Injections
Research Paper
DNA, Complementary
Caveolin
Genetic Vectors
Retinal ganglion
Retina
03 medical and health sciences
Downregulation and upregulation
Alpha-Globulins
medicine
Gene silencing
Animals
Ganglion cell layer
Intraocular Pressure
Brain-Derived Neurotrophic Factor
Retinal
Genetic Therapy
medicine.disease
eye diseases
Mice, Inbred C57BL
030104 developmental biology
Retinal Ganglion cells, Shp2 phosphatase
Focal Adhesion Kinase 1
sense organs
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 18387640
- Volume :
- 11
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....043a6f38aa76a9ede23f78b7158232b5