FIGURE 10.

Mechanism(s) leading to excessive generation of ROS following overexpression of MIOX under HG with ensuing increased apoptosis and synthesis of ECM fibronectin. MIOX overexpression (pcDNA transfection) in tubular cells generates excessive generation of ROS from dual sources (i.e. the NADPH oxidase system (NOX4) and mitochondria). ROS can activate TGF-β with consequential increased synthesis of ECM proteins, a process reminiscent of tubulo-interstitial fibrosis, whereas mitochondrial perturbations lead to MtDNA damage, leakage of cytochrome c, activation of caspase-3, and consequential apoptosis, changes that are reflective of tubular cell injury. Fibrosis and apoptosis are regarded as the major hallmarks of diabetic nephropathy.