Purchase this article with an account.
Koushik Mondal, Todd Lydic, Rajashekhar Gangaraju, Julia V Busik, Nawajes A Mandal; Modulation of Sphingolipid metabolites in Type 2 Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2681.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: Diabetic Retinopathy (DR), is one of the frightening enigmas in vision research. New approaches are required to understand the cause of DR and there is necessity for better clinical management. The objective of this study was to understand the role of sphingolipid signaling in DR.
Methods: Human cadaver retina from diabetic donors (n=8) and from donors with no history of diabetes (n=9) were obtained from National Disease Research Interchange (Philadelphia, PA). Sphingolipid profile from these retinas was determined by mass spectrometry (MS) and expression of sphingolipid metabolic, angiogenic and apoptotic marker genes were tested by qRT-PCR. The similar experiments were performed in primary human retinal endothelial cells (HREC), cultured in normal (5 mM Glucose) and hyperglycemic (25 mM Glucose) conditions in in-vitro studies.
In diabetic retina, we observed a decrease (25%) in Ceramide (Cer) level (p < 0.01), whereas the levels of Lactosylceramide (LacCer) doubled (p < 0.01). Like diabetic retina, a significant increase of LacCer (2-fold) was observed in hyperglycemic HREC cells in comparison with the cells cultured in control media (p < 0.05). Specifically, we observed an upregulation of short carbon chain LacCer species (C16:0) in both diabetic retina and in hyperglycemic HREC cells. By qRT-PCR, we observed significant downregulation in expression of de novo Cer biosynthetic enzyme, serine palmitoyl transferase 2 (SPTLC 2), cell death and inflammation marker FOS and DNA repair genes in both diabetic retina and hyperglycemic HREC cells. In hyperglycemic HREC, we detected increased expression of LacCer biosynthetic (B4GALT5 & B4GALT6), and cell adhesion molecule, platelet endothelial cell adhesion molecule-1 (PECAM1) genes. In agreement with our previous study, we observed a significant decrease in very long chain (VLC) polyunsaturated fatty acid biosynthetic gene (ELOVL4) in hyperglycemic HREC cells with concomitant decrease in very long chain Cer, LacCer and sphingomyelin (SM) species (C28:0, C28:1, C30:0 and C30:1).
Our analyses provided information that there is an association of sphingolipid metabolism with the pathogenesis of diabetic retinopathy as well as hyperglycemic HREC cells. Further research on de novo SL biosynthesis, LacCer, and VLC-sphingolipid metabolism and signaling pathways could offer novel findings for better understanding of DR pathology.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
This PDF is available to Subscribers Only