Sestrin 2 and AMPK connect hyperglycemia to Nox4-dependent endothelial nitric oxide synthase uncoupling and matrix protein expression.

摘要: Mesangial matrix accumulation is an early feature of glomerular pathology in diabetes. Oxidative stress plays a critical role hyperglycemia-induced injury. Here, we demonstrate that, mesangial cells (MCs), endothelial nitric oxide synthase (eNOS) uncoupled upon exposure to high glucose (HG), with enhanced generation reactive oxygen species (ROS) and decreased production oxide. Peroxynitrite mediates the effects HG on eNOS dysfunction. upregulates Nox4 protein, inhibition abrogates increase ROS peroxynitrite generation, as well uncoupling triggered by HG, demonstrating that functions upstream from eNOS. Importantly, this pathway contributes HG-induced MC fibronectin accumulation. Nox4-mediated dysfunction was confirmed glomeruli rat model type 1 Sestrin 2-dependent AMP-activated protein kinase (AMPK) activation attenuates synthesis through blockade Nox4-dependent subsequent uncoupling. We also find negatively regulates sestrin 2 AMPK, thereby promoting increased fibronectin. These data identify protective function for 2/AMPK potential targets intervention prevent fibrotic injury