Redox dependence of glomerular epithelial cell hypertrophy in response to glucose.
Podocytes or glomerular epithelial cells (GECs) are important targets of the diabetic microenvironment. Podocyte foot process effacement and widening, loss of GECs and hypertrophy are pathological features of this disease. ANG II and oxidative stress are key mediators of renal hypertrophy in diabetes. The cellular mechanisms responsible for GEC hypertrophy in diabetes are incompletely characterized. We investigated the effect of high glucose on protein synthesis and GEC hypertrophy. Exposure of GECs to high glucose dose dependently stimulated [(3)H]leucine incorporation, but not [(3)H]thymidine incorporation. High glucose resulted in the activation of ERK1/2 and Akt/PKB. ERK1/2 pathway inhibitor or the dominant negative mutant of Akt/PKB inhibited high glucose-induced protein synthesis. High glucose elicited a rapid generation of reactive oxygen species (ROS). The stimulatory effect of high glucose on ROS production, ERK1/2, and Akt/PKB activation was prevented by the antioxidants catalase, diphenylene iodonium, and N-acetylcysteine. Exposure of the cells to hydrogen peroxide mimicked the effects of high glucose. In addition, ANG II resulted in the activation of ERK1/2 and Akt/PKB and GEC hypertrophy. Moreover, high glucose and ANG II exhibited additive effects on ERK1/2 and Akt/PKB activation as well as protein synthesis. These additive responses were abolished by treatment of the cells with the antioxidants. These data demonstrate that high glucose stimulates GEC hypertrophy through a ROS-dependent activation of ERK1/2 and Akt/PKB. Enhanced ROS generation accounts for the additive effects of high glucose and ANG II, suggesting that this signaling cascade contributes to GEC injury in diabetes.
Kim
Nam-Ho
NH
University of Texas Health Science Center, Department of Medicine, Division of Nephrology, MC 7882, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Rincon-Choles
Hernan
H
Bhandari
Basant
B
Choudhury
Goutam Ghosh
GG
Abboud
Hanna E
HE
Gorin
Yves
Y
D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology*; D005947:Glucose / Q000494:pharmacology*; D006984:Hypertrophy; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology*; D007700:Kinetics; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D010084:Oxidation-Reduction; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D051381:Rats
D008353:Mannitol; D005947:Glucose