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Nader Sheibani, Qiong Huang, Eui Seok Shin, Christine M. Sorenson; High Glucose Promotes the Proapoptotic, Antimigratory Phenotype of Retinal Pericytes through Inhibition of Akt1and ERKs and Activation of JNK Pathways. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3552.
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To determine the impact of high glucose on retinal pericytes (PC).
Primary cultures of mouse retinal pericytes were maintained in medium containing either 5.7 mM D-glucose (low glucose; LG), 40.7 mM D-glucose (high glucose; HG), or 5.7 mM D-glucose and 35 mM L-glucose (osmotic control; LG+L-glu) for 5 days prior to each experiment. The cell proliferation assay was performed using EdU DNA labeling Click-iT EdU. Apoptotic cell death was assessed by TdT-dUTP Terminal Nick-End Labeling (TUNEL) staining or level of cleaved caspase 3. The impact of high glucose on migration of PC was assessed using transwell migration assay. The level of various signaling proteins was determined by Western blotting.
High glucose decreased the migration of retinal PC with a significant increase in the rate of apoptosis. High glucose minimally impacted the adhesion of retinal PC to various matrix proteins. The reduced migration of retinal PC under high glucose was reversed in the presence of the antioxidant N-acetylcysteine without a significant impact on the rate of apoptosis. The changes in PC migration and apoptosis under high glucose were concomitant with sustained activation of the downstream proapoptotic signaling pathway JNK1/MAPK and attenuation of prosurvival and promigratory, including the Akt1, MAPK/ERKs, and PDGFR-beta signaling pathways. Retinal PC under high glucose conditions also expressed increased levels of osteopontin and thrombospondin-1 (TSP1), proteins with pro-inflammatory and pro-proliferative activity in perivascular supporting cells.
The exposure of retinal PC to high glucose promotes a proapoptotic, antimigratory phenotype. Thus, alterations in the proangiogenic and proinflammatory properties of retinal PC during diabetes may contribute to the development and pathogenesis of diabetic retinopathy.
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