Figure 9

A cell type-dependent model of interactions between AT1 and Nox1, 2, and 4 in the human substantia nigra. The AT1 is broadly expressed in the CNS in astrocytes, microglia, and is particularly abundant in neurons, including dopamine neurons where, as we demonstrate here, the AT1 is found not only on the plasma membrane, but also intracellularly associated with the membranes of the endoplasmic reticulum, other cytoplasmic structures, nuclear membrane, and AT1 is found inside the nuclei themselves. The AT1 is also expressed by the vascular smooth muscle cells and by neutrophils and macrophages, raising the possibility that brain RAS activities can be influenced by the entry of peripheral monocyte-derived cells that are rich in AT1 and Nox2. The nuclear AT1, which we demonstrate here to be co-localized with nuclear Nox4, an event which frequency increases with disease progression, induces intra-nuclear production of reactive oxygen species (ROS, superoxide and hydrogen peroxide) leading to an increase in nucleic acid oxidation determined by increased levels of oxidized 8-OH guanosine (8-OHg). This complex landscape of AT1-Nox interactions, when balanced serves to maintain tissue homeostasis and normal levels of dopamine, but in chronic disease such as Parkinson’s the AngII/AT1/Nox4 axis might become overactive and lead to deleterious nucleic acid lesions that destabilize DNA and impair the transcriptional machinery in the affected neurons. Taken together, our findings suggest need for additional studies of these interactions toward designing therapies that restore healthy balance between the injurious and physiological functions of AT1 and Nox4 and by doing so moderate progression or prevent onset of neurodegenerative diseases. Legend: neurons – Nox4 (red), microglia – Nox2 (green), and astrocytes – mixture of Nox1 (yellow), Nox2 (green), and Nox4 (red).