Aging-Related Overactivity of the Angiotensin/AT1 Axis Decreases Sirtuin 3 Levels in the Substantia Nigra, Which Induces Vulnerability to Oxidative Stress and Neurodegeneration

Sirtuin 3 (SIRT3) and angiotensin play a major role in aging-related disorders. Both modulate oxidative stress and neurodegeneration. We investigated the interaction between SIRT3 and angiotensin II (AngII) in the dopaminergic system. Both in vivo and in vitro, treatment with AngII decreased SIRT3 expression, which was reversed by angiotensin type 1 receptor (AT1) antagonists. Aged animals showed enhanced pro-oxidative RAS activity and low nigral SIRT3 levels, which significantly increased with treatment with the AT1 antagonist candesartan or AT1 deletion. Consistent with this, AT2 knockout mice and cells treated with AT2 blockers showed downregulation of SIRT3. Treatment with the specific SIRT3 inhibitor AGK7 induced overexpression of AT1 and AT2 in substantia nigra (SN) of rats, and in dopaminergic neuronal MES23.5 and microglial N9 cell lines. The results suggest that SIRT3 may initially counteract low levels of oxidative stress as part of the antioxidant response. However, high or persistent oxidative stress induced by overactivation of the angiotensin/AT1 pro-oxidative axis induces a decrease in nigral SIRT3 levels. Furthermore, a decrease in SIRT3 levels further increases AT1 activity, which may lead to a feed-forward mechanism. This is observed in aged rats and can be counteracted by treatment with AT1 antagonists such as candesartan.