PKCδPromotes High Glucose Induced Renal Tubular Oxidative Damage via Regulating Activation and Translocation of p66Shc

Abstract

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Renal tubular injury by overproduction of ROS in mitochondria plays a critical role in the pathogenesis of DKD. Evidences have shown that p66Shc was involved in renal tubular injury via mitochondrial-dependent ROS production pathway, but little is known about the upstream signaling of p66Shc that leads to tubular oxidative damage under high glucose conditions. In this study, an increased PKCδand p66Shc activation and ROS production in renal tissues of patients with diabetic nephropathy were seen and further analysis revealed a positive correlation between the tubulointerstitial damage and p-PKCδ, p-p66Shc, and ROS production. In vitro, we investigated the phosphorylation and activation of p66Shc and PKCδduring treatment of HK-2 cells with high glucose (HG). Results showed that the activation of p66Shc and PKCδwas increased in a dose- and time-dependent manner, and this effect was suppressed by Rottlerin, a pharmacologic inhibitor of PKCδ. Moreover, PKCδsiRNA partially blocked HG-induced p66Shc phosphorylation, translocation, and ROS production in HK-2 cells. Taken together, these data suggest that activation of PKCδpromotes tubular cell injury through regulating p66Shc phosphorylation and mitochondrial translocation in HG ambient.