Increased hexokinase activity, of either ectopic or endogenous origin, protects renal epithelial cells against acute oxidant-induced cell death.
Glucose (Glc) metabolism protects cells against oxidant injury. By virtue of their central position in both Glc uptake and utilization, hexokinases (HKs) are ideally suited to contribute to these effects. Compatible with this hypothesis, endogenous HK activity correlates inversely with injury susceptibility in individual renal cell types. We recently reported that ectopic HK expression mimics the anti-apoptotic effects of growth factors in cultured fibroblasts, but anti-apoptotic roles for HKs have not been examined in other cell types or in a cellular injury model. We therefore evaluated HK overexpression for the ability to mitigate acute oxidant-induced cell death in an established epithelial cell culture injury model. In parallel, we examined salutary heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) treatment for the ability to 1) increase endogenous HK activity and 2) mimic the protective effects of ectopic HK expression. Both HK overexpression and HB-EGF increased Glc-phosphorylating capacity and metabolism, and these changes were associated with markedly reduced susceptibility to acute oxidant-induced apoptosis. The uniform Glc dependence of these effects suggests an important adaptive role for Glc metabolism, and for HK activity in particular, in the promotion of epithelial cell survival. These findings also support the contention that HKs contribute to the protective effects of growth factors.
Bryson
Jane M
JM
Department of Medicine, College of Medicine, University of Illinois, Chicago 60612, USA.
Coy
Platina E
PE
Gottlob
Kathrin
K
Hay
Nissim
N
Robey
R Brooks
RB
D000256:Adenoviridae / Q000235:genetics; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016877:Oxidants / Q000494:pharmacology*; D010766:Phosphorylation
C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016877:Oxidants; D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; D006593:Hexokinase; D005947:Glucose