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Título

ANXA1 PARTICIPATES IN THE PATHOGENESIS OF MURINE AND HUMAN DIABETIC RETINOPATHY

Resumo

In diabetic retinopathy (DR), retinal gliosis occurs characterized by increased expression of glial fibrillary acidic protein (GFAP) and reduced activity of glutamine synthetase (GS). The specific involvement and mechanisms of action of annexin A1 (AnxA1), in the context of DR have not been thoroughly investigated yet.Objective: Investigate the involvement of AnxA1 in the development of DR. Metodology: Wild Type+/+ and AnxA1-/- C57BL/6 mice were used to induce DR over a 12-week period using streptozotocin. Expression of GFAP, GS, AnxA1, cleaved caspase 3 were evaluated by western blotting in retina. In addition, in silico analysis was conducted using GSE111465 (6-week DR animal model) and GSE160306 (human retina with different stages of DR). Results: The participation of ANXA1 in human DR was analyzed using the dataset GSE160306. Levels of ANXA1 transcripts in the human retina increase with the severity of DR, with significantly higher expression in higher scores compared to lower scores. Additionally, ANXA1 expression was higher in the retinal periphery compared to the macula. In another dataset (GSE160306), after 6 weeks of STZ-induced diabetes, murine retinas showed increased levels of AnxA1 transcripts compared to controls. The expression of ANXA1 protein in mouse retinas with DR and controls was evaluated using western blotting. There was a significant increase in ANXA1 levels in the RD group retinas compared to controls. Moreover, significantly higher expression of GFAP and Vimentin was observed in ANXA1+/+ mouse retinas with RD compared to controls, but no difference was observed in ANXA1-/- mouse retinas. The activation of the transcription factor STAT3 was also investigated, showing a significant increase in pSTAT3 levels in ANXA1+/+ RD group retinas compared to controls, while no change was observed in ANXA1-/- retinas. Additionally, ANXA1+/+ animals with RD showed higher expression of cleaved caspase 3 compared to their controls. There were no changes in caspase 3 expression in ANXA1-/- retinas. On the other hand, ANXA1-/- retinas from the RD group animals showed elevated levels of GS compared to ANXA1+/+ retinas. Conclusion: ANXA1 is involved in the progression of human DR and participates in processes related to the development of RD, such as regulating gliosis in mice. Thus, AnxA1 represents a potential target for the development of new therapeutic strategies for DR.

Referências Bibliográficas

FERREIRA, L. P. S et al. Annexin A1, A2, A5, and A6 involvement in human pathologies. Proteins, May 23 2023.

DA SILVA, R.A et al. Annexins as potential targets in ocular diseases. Drug Discov Today, v. 27, n. 11, p. 103367, Nov 2022.

CARPI-SANTOS, R. et al. Contribution of Müller Cells in the Diabetic Retinopathy Development: Focus on Oxidative Stress and Inflammation. Antioxidants (Basel), v. 11, n. 4, Mar 23 2022.