New insights into the mechanisms of action of topical administration of GLP-1 in an experimental model of diabetic retinopathy
Sampedro, Joel (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Solà-Adell, Cristina (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Turch-Anguera, Mireia (Hospital Universitari Vall d'Hebron)
Valeri, Marta (Hospital Universitari Vall d'Hebron)
Simó-Servat, Olga (Universitat Autònoma de Barcelona. Departament de Medicina)
Lagunas, Carmen (Ferrer Advanced Biotherapeutics)
Simó Canonge, Rafael (Universitat Autònoma de Barcelona. Departament de Medicina)
Hernández, Cristina (Hospital Universitari Vall d'Hebron)
Bogdanov, Patricia (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Ramos, Hugo (Hospital Universitari Vall d'Hebron)

Data:	2019
Resum:	The main goals of this work were to assess whether the topical administration of glucagon-like peptide-1 (GLP-1) could revert the impairment of the neurovascular unit induced by long-term diabetes (24 weeks) in diabetic mice and to look into the underlying mechanisms. For that reason, db/db mice were treated with eye drops of GLP-1 or vehicle for 3 weeks. Moreover, db/+ mice were used as control. Studies performed in vivo included electroretinogramand the assessment of vascular leakage by using Evans Blue. NF-κB, GFAP and Ki67 proteins were analyzed by immunofluorescence (IF). Additionally, caspase 9, AMPK, IKBα, NF-κB, AKT, GSK3, β-catenin, Bcl-xl, and VEGF were analyzed by WB. Finally, VEGF, IL-1β, IL-6, TNF-α, IL-18, and NLRP3 were studied by reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. We found that topical administration of GLP-1 reverted reactive gliosis and albumin extravasation, and protected against apoptosis and retinal dysfunction. Regarding the involved mechanisms, GLP-1 exerted an anti-inflammatory action by decreasing NF-κB, inflammosome, and pro-inflammatory factors. In addition, it also decreased VEGF expression. Furthermore, GLP-1 promoted cell survival by increasing the anti-apoptotic protein Bcl-xl and the signaling pathway kt/GSK3b/β-catenin. Finally, Ki67 results revealed that GLP-1 treatment could induce neurogenesis. In conclusion, the topical administration of GLP-1 reverts the impairment of the neurovascular unit by modulating essential pathways involved in the development of diabetic retinopathy (DR). These beneficial effects on the neurovascular unit could pave the way for clinical trials addressed to confirm the effectiveness of GLP-1 in early stages of DR.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Diabetic retinopathy ; Glucagon-like peptide-1 ; Retinal neurodegeneration ; Experimental diabetes
Publicat a:	Journal of clinical medicine, Vol. 8 (2019) , p. 1-20, ISSN 2077-0383

DOI: 10.3390/jcm8030339
PMID: 30862093

20 p, 8.4 MB

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