Fig. 2.

Crosstalk between different sources of reactive oxygen and nitrogen species (mitochondria, NADPH oxidases, xanthine oxidase (XO) and nitric oxide (NO) synthase). Hyperglycemia and obesity lead to activation of primary ROS sources such as mitochondria (mtROS, due to metabolic dysregulation) and NADPH oxidases (Nox-derived ROS, due to low-grade inflammation). Signaling by advanced glycation end products (AGE) and their receptor (RAGE) might also trigger the activation of NADPH oxidases. These primary ROS sources can activate each other in a crosstalk fashion via so-called “kindling radicals” with the potential involvement of redox-sensitive mitochondrial pores (mPTP, mitochondrial permeability transition pore and mK_ATP, mitochondrial ATP-sensitive potassium channel) and protein kinases (PKC). Primary ROS from mitochondria and Nox enzymes can also activate secondary ROS sources such as xanthine oxidase (by oxidative conversion from the dehydrogenase form) and uncoupled nitric oxide synthases (by uncoupling via several redox switches). The ROS-induced ROS formation can initiate vicious circles that further aggravate the disease progression and stimulate AGE/RAGE signaling as well as low-grade inflammation.

Modified from Biochim Biophys Acta 1797 (2010) 897–906. With permission by Elsevier.