Acute hyperglycemia-induced cellular alterations in human proximal tubule epithelial cells

Date

2010-05

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Abstract

Studies have shown that prolonged exposure of hyperglycemia may injure cells and contribute in the development of renal diseases in diabetes. However, the mechanisms leading to renal abnormalities remain unclear. Cell death by apoptosis is tightly coordinated under the control of genetic programs. Previously, Samikkannu et al. demonstrated that acute (10-20 min) exposure of human proximal tubule epithelial cells (hPTEC) to high glucose (25 mM) induces a time-dependent dual effect, involving an early proliferation and a late apoptosis (Am. J. Physiol. 291: F162-F175, 2006). Acute exposure of high glucose initiated intrinsic apoptotic pathway activated by ROS. Consistent with these observations, we observed increased protein expression and serine 20, 46 and 392 phosphorylation of p53 that was inhibited by ROS inhibitor NAC. Under similar conditions high glucose also induced apoptosis. Treatment with conditioned medium inhibited the early phase of cell proliferation and induced an early p53 phosphorylation that was inhibited by ROS inhibitor NAC. In addition, we observed increased chromatin condensation and DNA fragmentation. However, in HG (acute) treated cells replenishment with fresh normal glucose medium at 6h induced only cell proliferation further confirming the role of secretory factor(s). Consistent with these results, we observed decreased ROS production, DNA fragmentation, and chromatin condensation. Although additional studies are needed to identify HG mediated secretory factor(s) this study demonstrates for the first time that a single HG exposure for 20 min alone is sufficient to induce cellular factor(s) capable of eliciting ROS mediated cellular apoptosis leading to epithelial cell dysfunction. However in normal physiology renal excretory pathways may protect the renal epithelial cells from transient hyperglycemia induced jury. Supported by NIH DK072140-01A1S

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Keywords

Hyperglycemia, Epithelial cells

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