Aging, Angiotensin system and dopaminergic degeneration in the substantia nigra.

For years, the renin-angiotensin system (RAS) was described as a circulating humoral system that regulates blood pressure and water homeostasis. Angiotensin II (AII) is the most important effector peptide. However, in addition to the "classical" humoral RAS there exist local RAS in many tissues and locally formed AII activates NADPH-dependent oxidases, which are a major source of superoxide and are upregulated in major aging-related diseases such as hypertension, diabetes and atherosclerosis. Accordingly, disruption of AII receptors promotes longevity in mice. The brain has an independent local RAS, which was also initially associated with the central control of blood pressure. However, more recent studies have involved brain RAS in brain disorders, including neurodegenerative diseases. The interaction between AII and dopamine is particularly interesting. Recent evidence suggests that dopamine and AII systems directly counterregulate each other in renal cells as well as in the striatum and substantia nigra. Dopamine depletion may induce RAS upregulation as a potential compensatory mechanism. However, RAS hyperactivation also exacerbates NADPH-oxidase activity, oxidative stress and the microglial inflammatory response and contribute to progression of dopaminergic neuron loss, as observed in recent studies with animal models of Parkinson's disease (PD). Aging is the most prominent risk factor for PD and other neurodegenerative diseases. Interestingly, we observed increased activation of the NADPH oxidase complex and increased levels of the pro-inflammatory cytokines in the nigra of aged male rats, which was associated with increased RAS activity and was reduced by treatment with AII antagonists. We also observed that the lack of oestrogen may act as an additional factor for increasing RAS activity in the nigra in aged females, which was significantly reduced by treatment with AII antagonists. Manipulation of the brain RAS may constitute an effective neuroprotective strategy against the aging-related risk of dopaminergic degeneration.