High salt induces cognitive impairment via the interaction of the angiotensin II‐AT<sub>1</sub> and prostaglandin E2‐EP<sub>1</sub> systems
Hisayoshi Kubota, Kazuo Kunisawa, Bolati Wulaer, Masaya Hasegawa, Hitomi Kurahashi, Takatoshi Sakata, Hiroyuki Tezuka, Masanori Kugita, Shizuko Nagao, Taku Nagai, Tomoyuki Furuyashiki, Shuh Narumiya, Kuniaki Saito, Toshitaka Nabeshima, Akihiro Mouri
Abstract
Background and Purpose High salt (HS) intake has been associated with hypertension and cognitive impairment. It is well known that the angiotensin II (Ang II)‐AT 1 receptor and prostaglandin E2 (PGE2)‐EP 1 receptor systems are involved in hypertension and neurotoxicity. However, the involvement of these systems in HS‐mediated hypertension and emotional and cognitive impairments remains unclear. Experimental Approach Mice were loaded with HS solution (2% NaCl drinking water) for 12 weeks, and blood pressure was monitored. Subsequently, effects of HS intake on emotional and cognitive function and tau phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP) were investigated. The involvement of Ang II‐AT 1 and PGE2‐EP 1 systems in HS‐induced hypertension and neuronal and behavioural impairments was examined by treatment with losartan, an AT 1 receptor blocker (ARB), or EP 1 gene knockout. Key Results We demonstrate that hypertension and impaired social behaviour and object recognition memory following HS intake may be associated with tau hyperphosphorylation, decreased phosphorylation of Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII), and postsynaptic density protein 95 (PSD95) expression in the PFC and HIP of mice. These changes were blocked by pharmacological treatment with losartan or EP 1 receptor gene knockout. Conclusions and Implications Our findings suggest that the interaction of Ang II‐AT 1 receptor and PGE2‐EP 1 receptor systems could be novel therapeutic targets for hypertension‐induced cognitive impairment.