VEGF and ELAVL1/HuR protein levels are increased in dry and wet AMD patients. A new tile in the pathophysiologic mechanisms underlying RPE degeneration?

• Published in: Pharmacological research Vol. 208; p. 107380
• Main Authors: Bresciani, Giorgia, Manai, Federico, Felszeghy, Szabolcs, Smedowski, Adrian, Kaarniranta, Kai, Amadio, Marialaura
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.10.2024; Elsevier
• Subjects: Aged; Aged, 80 and over; AMD; Animals; ELAV-Like Protein 1 - genetics; ELAV-Like Protein 1 - metabolism; Female; Geographic Atrophy - metabolism; Humans; HuR; Macular Degeneration - metabolism; Macular Degeneration - pathology; Macular Degeneration - physiopathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Retina; Retinal Pigment Epithelium - metabolism; RPE; Vascular Endothelial Growth Factor A - metabolism; VEGF; Wet Macular Degeneration - genetics; Wet Macular Degeneration - metabolism; AMD; Retina; HuR; Nrf2; VEGF; RPE
• ISSN: 1043-6618; 1096-1186; 1096-1186
• DOI: 10.1016/j.phrs.2024.107380

Age-related macular degeneration (AMD) is a common retinal pathology characterized by degeneration of macula’s retinal pigment epithelium (RPE) and photoreceptors, visual impairment, or loss. Compared to wet AMD, dry AMD is more common, but lacks cures; therefore, identification of new potential therapeutic targets and treatments is urgent. Increased oxidative stress and declining antioxidant, detoxifying systems contribute to the pathophysiologic mechanisms underlying AMD. The present work shows that the Embryonic Lethal Abnormal Vision-Like 1/Human antigen R (ELAVL1/HuR) and the Vascular Endothelial Growth Factor (VEGF) protein levels are higher in the RPE of both dry and wet AMD patients compared to healthy subjects. Moreover, increased HuR protein levels are detected in the retina, and especially in the RPE layer, of a dry AMD model, the nuclear factor erythroid 2-related factor 2 (Nrf2) / peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) double knock-out mouse. The crosstalk among Nrf2, HuR and VEGF has been also studied in ARPE-19 cells in basal and stressful conditions related to the AMD context (i.e., oxidative stress, autophagy impairment, Nrf2 deficit), offering new evidence of the mutual influence between Nrf2 and HuR, of the dependence of VEGF expression and secretion by these two factors, and of the increased susceptibility of cells to stressful conditions in Nrf2- or HuR-impaired contexts. Overall, this study shows evidence of the interplay among Nrf2, HuR and VEGF, essential factors for RPE homeostasis, and represents an additional piece in the understanding of the complex pathophysiologic mechanisms underlying AMD. [Display omitted] •Both Nrf2 and HuR silencing treatments, given singularly, dampen VEGF gene expression and protein release in ARPE-19 cells.•Silencing treatments against Nrf2 and HuR induce specific susceptibility to different stress stimuli in ARPE-19 cells.•Stressed siNrf2 cells show higher HuR protein–VEGF mRNA binding and VEGF release suggesting that HuR compensates Nrf2 lack.•Nrf2/PGC-1α double KO mouse model of dry AMD displays up-regulated expression of HuR protein levels in the retina.•VEGF and HuR protein levels are increased in RPE of dry and wet AMD patients compared with healthy subjects