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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/F1399    most recent 00051.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Thamilselvan, V. Articles by Thamilselvan, S. PubMed PubMed Citation Articles by Thamilselvan, V. Articles by Thamilselvan, S.

Oxalate-induced activation of PKC- and - regulates NADPH oxidase-mediated oxidative injury in renal tubular epithelial cells

Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan

Submitted January 29, 2009 ; accepted in final form August 14, 2009

Oxalate-induced oxidative stress contributes to cell injury and promotes renal deposition of calcium oxalate crystals. However, we do not know how oxalate stimulates reactive oxygen species (ROS) in renal tubular epithelial cells. We investigated the signaling mechanism of oxalate-induced ROS formation in these cells and found that oxalate significantly increased membrane-associated protein kinase C (PKC) activity while at the same time lowering cytosolic PKC activity. Oxalate markedly translocated PKC- and - from the cytosol to the cell membrane. Pretreatment of LLC-PK₁ cells with specific inhibitors of PKC- or - significantly blocked oxalate-induced generation of superoxide and hydrogen peroxide along with NADPH oxidase activity, LDH release, lipid hydroperoxide formation, and apoptosis. The PKC activator PMA mimicked oxalate's effect on oxidative stress in LLC-PK₁ cells as well as cytosol-to-membrane translocation of PKC- and -. Silencing of PKC- expression by PKC--specific small interfering RNA significantly attenuated oxalate-induced cell injury by decreasing hydrogen peroxide generation and LDH release. We believe this is the first demonstration that PKC-- and --dependent activation of NADPH oxidase is one of the mechanisms responsible for oxalate-induced oxidative injury in renal tubular epithelial cells. The study suggests that the therapeutic approach might be considered toward attenuating oxalate-induced PKC signaling-mediated oxidative injury in recurrent stone formers.

protein kinase C; oxidative stress; calcium oxalate; kidney stone; urolithiasis