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H. Yokouchi, K. Yasuda, N. Takeda, Y. Kaburagi, S. Yamamoto; Angiopoietin-Like Protein 4 (angptl4) Is Induced by High Glucose in Retinal Pigment Epithelial Cells and Exhibits Potent Angiogenic Activity on Retinal Endothelial Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3399.
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© ARVO (1962-2015); The Authors (2016-present)
Hyperglycemia has been established as a major risk factor for diabetic retinopathy (DR).The progression of DR is mainly related to a local imbalance of pro- versus anti-angiogenic factors in the retina. We have hypothesized that angiogenic factors are released from retinal pigment epithelial (RPE) cells cultured under high glucose (HG) conditions.
Cultured human retinal endothelial (RE) cells were exposed to culture medium of ARPE-19 cells grown in a HG medium to determine whether RPE cells released factors that promote tube formation. For transcriptome analysis, the expression profiles of ARPE-19 cells cultured under HG conditions were determined by GeneChip (Affymetrix). We investigated whether ANGPTL4 was a major angiogenic factor released from ARPE-19 cells under HG conditions by experiments of recombinant protein, conditioned medium (CM) from ARPE-19 cells and RNA interference (RNAi), using cultured human RE cells as the test system.
The CM from ARPE-19 cells cultured under HG conditions promoted tube formation of cultured human RE cells. GeneChip analysis showed that ANGPTL4 was one of the most up-regulated genes under HG conditions. In addition, recombinant ANGPTL4 promoted all of the elements of angiogenesis; cell invasion, migration, proliferation, and tube formation in human RE cells at the comparable effect to VEGF in vitro. The results of experiments using CM from ARPE-19 cells and RNAi combined demonstrated that ANGPTL4 was a major angiogenic factor released from ARPE-19 cells under HG conditions.
Our results demonstrated that the induction of the angiogenic activity by HG in ARPE-19 cells was mainly mediated by an up-regulation of ANGPTL4 expression. Although in vivo validation is necessary in human diabetes patients, our data suggest that RPE cells might contribute to the pathogenesis of DR via up-regulated expression of ANGPTL4. These findings may have many novel implications in relation to clinical aspects of DR.
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