Abstract
Purpose :
Early biochemical and molecular changes in the pathogenesis of diabetic retinopathy occur in both the retina and leukocytes. Montelukast, an anti-inflammatory drug, prevents diabetes-induced acellular capillary formation in the mouse retina. However, the molecular pathways underlying the pathogenesis of diabetic retinopathy and regulated by montelukast are not fully understood.
Methods :
RNA sequencing was performed for retinas and leukocytes from 1) 12-week-diabetic mice and 2) diabetic mice treated with montelukast from the onset of diabetes and compared the differential expression of transcripts with that of 3) non-diabetic mice (ND).
Results :
Compared to retinas from ND mice, diabetes caused significant down regulation of transcripts involving visual function (Cryba4, Crygs, Lrat, Rpe65) and upregulation of transcripts regulating vascular permeability (Fgfbp3), the cell death pathway (WDr31 and Fos of apoptosis; Cathepsin C of pyroptosis; and Calpain II of necrosis), and glucose metabolism (Ide) (FDR-adjusted P <0.0103 for all comparisons). Compared to leukocytes from ND mice, diabetes resulted in upregulation of the leukotriene cascade (Ltb4r1), the cytokine and the chemokine signaling pathway mediating inflammation (Tnfrsf1b, Tnfrsf8, Ccr2), and apoptosis (Tnfrsf21) while transcripts that regulate oxidative stress (Gpx4, Srxn1), anti-inflammatory processes and neuronal repair (Cxcl5) were down regulated (FDR-adjusted P <0.05 for all comparisons). Treatment with montelukast prevented diabetes-induced alterations in transcripts of glucose metabolism, vascular permeability, and apoptosis, but not visual function, in the retina and, specifically, oxidative stress in leukocytes (FDR-adjusted P <0.05 for all comparisons).
Conclusions :
Montelukast prevents many diabetes-induced alterations in gene expression in both the retina and leukocytes in mice.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.