title: Acute effect of high glucose on long-term cell growth: a role for transient glucose increase in proximal tubule cell injury.
abstract: Although chronic exposure of renal cells to high glucose has been shown to cause cell injury, the effect of acute exposure has not been elucidated. In this study, we demonstrate that acute (10 min) exposure of human proximal tubule epithelial cells (hPTEC) to high glucose (25 mM) induces a time-dependent dual effect consisting of an early proliferation and a late apoptosis. Acute exposure of hPTEC to high glucose induced a twofold increase in DNA synthesis and cell number at 12 h. However, after 36 h, a significant decrease in cell growth is observed, followed by apoptosis. On glucose treatment, both p42/p44 mitogen-activated protein (MAP) kinases and the downstream signaling intermediate NF-kappaB were phosphorylated and translocated to the nucleus. Pretreatment of cells with MAP kinase and NF-kappaB-specific inhibitors abolished glucose-induced proliferation. However, these inhibitors were ineffective in preventing glucose-induced apoptosis. Interestingly, conditioned medium from cells exposed to high-glucose concentrations inhibited proliferation and concomitantly induced apoptosis in normal cells, suggesting that the inhibitory effect of glucose occurs through secretion of a secondary factor(s). In parallel to apoptosis, we observed an increased production of reactive oxygen species (ROS). Pretreatment of cells with the antioxidant N-acetyl cysteine reversed glucose-mediated ROS production and apoptosis, suggesting that ROS is involved in apoptosis. Our study demonstrates for the first time that a single high-glucose exposure for 10 min alone is sufficient to elicit proliferation and apoptosis in hPTEC and suggests that episodes of transient increase in glucose may contribute to cell damage leading to epithelial cell dysfunction.
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1300 Coulter Drive, Amarillo, TX 79106, USA.
authors.forename: Thangavel
authors.initials: T
authors.lastname: Samikkannu
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Thomas
authors.forename: G Jayarama
authors.initials: GJ
authors.lastname: Bhat
authors.forename: Vaughan
authors.initials: V
authors.lastname: Wittman
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Thekkumkara
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D003928:Diabetic Nephropathies / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000502:physiology*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000032:analysis / Q000502:physiology; D016328:NF-kappa B / Q000032:analysis / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose