Transcriptomic Analysis Reveals That Retinal Neuromodulation Is a Relevant Mechanism in the Neuroprotective Effect of Sitagliptin in an Experimental Model of Diabetic Retinopathy
Ramos, Hugo (Hospital Universitari Vall d'Hebron)
Bogdanov, Patricia (Hospital Universitari Vall d'Hebron)
Simó Canonge, Rafael (Hospital Universitari Vall d'Hebron)
Deàs-Just, Anna (Hospital Universitari Vall d'Hebron)
Hernández, Cristina (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	Synaptic dysfunction and neuronal damage have been extensively associated with diabetic retinopathy (DR). Our group evidenced that chronic hyperglycemia reduces the retinal expression of presynaptic proteins, which are crucial for proper synaptic function. The aim of the study was to explore the effect of topically administered sitagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4, on the retinal expression patterns of an experimental model of DR. Transcriptome analysis was performed, comparing the retinas of 10 diabetic (db/db) mice randomly treated with sitagliptin eye drops (10 mg/mL) twice daily and the retinas of 10 additional db/db mice that received vehicle eye drops. Ten non-diabetic mice (db/+) were used as a control group. The Gene Ontology (GO) and Reactome databases were used to perform the gene set enrichment analysis (GSEA) in order to explore the most enriched biological pathways among the groups. The most differentiated genes of these pathways were validated through quantitative RT-PCR. Transcriptome analysis revealed that sitagliptin eye drops have a significant effect on retinal expression patterns and that neurotransmission is the most enriched biological process. Our study evidenced enriched pathways that contain genes involved in membrane trafficking, transmission across chemical synapses, vesicle-mediated transport, neurotransmitter receptors and postsynaptic signal transmission with negative regulation of signaling as a consequence of neuroprotector treatment with sitagliptin. This improves the modulation of the macromolecule biosynthetic process with positive regulation of cell communication, which provides beneficial effects for the neuronal metabolism. This study suggests that topical administration of sitagliptin ameliorates the abnormalities on presynaptic and postsynaptic signal transmission during experimental DR and that this improvement is one of the main mechanisms behind the previously demonstrated beneficial effects.
Ajuts:	Agencia Estatal de Investigación PID2019-104225RB-I00 Instituto de Salud Carlos III PI19/01215 Instituto de Salud Carlos III ICI20/00129
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 ; Differentially expressed RNAs ; Dipeptidyl peptidase-4 inhibitors ; Sitagliptin ; Synaptic signal transmission
Publicat a:	International journal of molecular sciences, Vol. 24 (december 2022) , ISSN 1422-0067

DOI: 10.3390/ijms24010571
PMID: 36614016

17 p, 4.5 MB

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