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Am J Physiol Cell Physiol 284: C1374-C1386, 2003. First published January 22, 2003; doi:10.1152/ajpcell.00466.2002
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Vol. 284, Issue 6, C1374-C1386, June 2003

High glucose and endothelial cell growth: novel effects independent of autocrine TGF-beta 1 and hyperosmolarity

S. McGinn1, P. Poronnik1,3, M. King2, E. D. M. Gallery1, and C. A. Pollock1

1 Department of Medicine, Kolling Institute: Renal Research Group, and 2 Department of Immunology, Royal North Shore Hospital, St Leonards, 2065; and 3 Department of Physiology, University of Sydney, New South Wales 2006, Australia

Human endothelial cells were exposed to 5 mM glucose (control), 25 mM (high) glucose, or osmotic control for 72 h. TGF-beta 1 production, cell growth, death, and cell cycle progression, and the effects of TGF-beta 1 and TGF-beta neutralization on these parameters were studied. High glucose and hyperosmolarity increased endothelial TGF-beta 1 secretion (P < 0.0001) and bioactivity (P < 0.0001). However, high glucose had a greater effect on reducing endothelial cell number (P < 0.001) and increasing cellular protein content (P < 0.001) than the osmotic control. TGF-beta antibody only reversed the antiproliferative and hypertrophic effects of high glucose. High glucose altered cell cycle progression and cyclin-dependent kinase inhibitor expression independently of hyperosmolarity. High glucose increased endothelial cell apoptosis (P < 0.01), whereas hyperosmolarity induced endothelial cell necrosis (P < 0.001). TGF-beta antibody did not reverse the apoptotic effects observed with high glucose. Exogenous TGF-beta 1 mimicked the increased S phase delay but not endoreduplication observed with high glucose. High glucose altered endothelial cell growth, apoptosis, and cell cycle progression. These growth effects occurred principally via a TGF-beta 1 autocrine pathway. In contrast, apoptosis and endoreduplication occurred independently of this cytokine and hyperosmolarity.

endothelial cells; diabetes mellitus; apoptosis; endoreduplication; transforming growth factor-beta 1


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