ADAM17/ACE2 interaction mediates cadmium-induced brain damage and neuroinflammation in Wistar rats

Angiotensin-converting enzyme 2 (ACE2) is a critical component in the renin-angiotensin system. A Disintegrin And Metalloprotease 17 (ADAM17) is the first identified sheddase for common inflammatory cytokines. Changes in ACE2 expression and its biological activity facilitated by ADAM17 are involved in several diseases including neurodegenerative disorders. Herein, the study investigated an innovative viewpoint on cadmium (Cd)-induced neurotoxicity and explored whether ADAM17/ACE2 interplay mediated the Cd-induced brain injury and neuroinflammation. For this aim, 32 adult male Wistar rats were included and randomly grouped. Eight rats served as a control group and the remaining 24 experimental rats were exposed to Cd (5 mg/kg/day, orally, 21 days); assigned as either Cd-alone (Cd group), received ADAM17 inhibitor [TAPI-1, 10 mg/kg, intraperitoneal] (Cd/TAPI-1 group), or received vitamin E, 100 mg/kg/d, orally (Cd/vit E group). Ultimately, the brains were harvested and exposed to biochemical, histological, and immunohistochemical (IHC) studies for measuring oxidative stress and inflammatory markers, histopathological examination, and for IHC identification of ADAM17, ACE2, and glial fibrillary acidic protein (GFAP). Cd resulted in biochemical disturbances in the inflammatory and oxidative stress markers, degenerative histopathological changes in the cerebral cortex and hippocampus, and enhanced ADAM17 and GFAP expression, meanwhile downregulated ACE2 expression. Vitamin E showed a superior effect in maintaining the oxidative/antioxidant-balanced defense system. However, the biochemical and histological changes in the brain were more effectively alleviated by TAPI-1 administration than by the partial improvement made by vitamin E therapy. These observations suggested that oxidative stress was involved in Cd-mediated upregulation of ADAM17 and ACE2 shedding. It was concluded that oxidative stress, at least in part, resulted in ADAM17-mediated ACE2 cleavage in the current Cd-induced brain damage.