Excess salt causes cerebral neuronal apoptosis and inflammation in stroke-prone hypertensive rats through angiotensin II-induced NADPH oxidase activation.
OBJECTIVE
The precise mechanism of salt-induced brain injury is unclear. We examined the detailed causative role of angiotensin II and NADPH oxidase in salt-accelerated brain injury of stroke-prone spontaneously hypertensive rats (SHRSP).


METHODS
We examined the effect of salt loading on brain reactive oxygen species (ROS), inflammation, and apoptosis in SHRSP. Salt-loaded SHRSP were given vehicle, valsartan (an angiotensin AT1 receptor blocker), or hydralazine to compare their efficacy on brain injury. We also examined the efficacy of apocynin (a NADPH oxidase inhibitor) on brain injury of salt-loaded SHRSP.


RESULTS
Cerebral NADPH oxidase activity and ROS in SHRSP were already increased at 1 week after salt loading followed by the significant increase in ED-1-positive cells and neuronal apoptosis. Thus, cerebral NADPH oxidase activation preceded cerebral inflammation and neuronal apoptosis. Despite comparable hypotensive effects between valsartan and hydralazine in salt-loaded SHRSP, valsartan reduced cerebral NADPH oxidase activity and ROS more than hydralazine being accompanied by more prevention of stroke by valsartan than hydralazine. Valsartan, but not hydralazine, prevented neuronal apoptosis, being associated with the suppression of apoptosis signal-regulating kinase 1 activation by valsartan. Moreover, cerebral inflammation was also prevented by valsartan more than hydralazine, being associated with more suppression of monocyte chemotactic protein-1 and tumor necrosis factor-alpha expressions by valsartan. Thus, angiotensin II was directly involved in salt-induced neuronal NADPH oxidase activation, ROS, apoptosis, and inflammation in SHRSP. Apocynin attenuated the enhancement of ROS, cerebral inflammation, neuronal apoptosis, and apoptosis signal-regulating kinase 1 activation and prevented stroke in salt-loaded SHRSP, indicating the causative role of cerebral NADPH oxidase in salt-induced brain injury.


CONCLUSIONS
We obtained the evidence that excess salt, through ROS produced by angiotensin II-activated NADPH oxidase, caused cerebral neuronal apoptosis and inflammation as well as stroke in SHRSP.
Yamamoto
Eiichiro
E
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Tamamaki
Nobuaki
N
Nakamura
Taishi
T
Kataoka
Keiichiro
K
Tokutomi
Yoshiko
Y
Dong
Yi-Fei
YF
Fukuda
Masaya
M
Matsuba
Shinji
S
Ogawa
Hisao
H
Kim-Mitsuyama
Shokei
S
D000098:Acetophenones / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects / Q000473:pathology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017382:Reactive Oxygen Species / Q000378:metabolism; D012965:Sodium Chloride / Q000008:administration & dosage / Q000009:adverse effects*; D020521:Stroke / Q000473:pathology / Q000503:physiopathology; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D000098:Acetophenones; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D000804:Angiotensin II; D006830:Hydralazine; D012965:Sodium Chloride; D000068756:Valsartan; C056165:acetovanillone; D019255:NADPH Oxidases; D014633:Valine