Exaggeration of focal cerebral ischemia in transgenic mice carrying human Renin and human angiotensinogen genes.
OBJECTIVE
We examined the possibility that activation of the human brain renin-angiotensin system is involved in enhancement of ischemic brain damage using chimeric transgenic mice with human renin (hRN) and human angiotensinogen (hANG) genes.


METHODS
Chimeric (hRN/hANG-Tg) mice were generated by mating of hRN and hANG transgenic mice. Permanent occlusion of the middle cerebral artery (MCA) by an intraluminal filament technique induced focal ischemic brain lesions.


RESULTS
hRN/hANG-Tg mice showed higher angiotensin II levels in the plasma and brain. The ischemic brain area at 24 hours after MCA occlusion was significantly enlarged in hRN/hANG-Tg mice with an enhanced neurological deficit compared to that in wild-type, hRN-Tg and hANG-Tg mice. The reduction of cerebral blood flow in the periphery region of the MCA territory after MCA occlusion was markedly exaggerated in hRN/hANG-Tg mice. Superoxide anion production in the brain and arteries was also increased significantly in hRN/hANG-Tg mice even before MCA occlusion and was further enhanced after MCA occlusion. Treatment with an AT(1) receptor blocker, valsartan (3.0 mg/kg per day), for 2 weeks significantly reduced the ischemic brain area and improved the neurological deficit after MCA occlusion in hRN/hANG-Tg mice, similar to those in wild-type, hRN-Tg, and hANG-Tg mice, with restoration of cerebral blood flow in the peripheral region and decreases in superoxide anion production and blood pressure.


CONCLUSIONS
These results indicate that activation of the human renin-angiotensin system exaggerates ischemic brain damage mainly through stimulation of the AT(1) receptor and marked reduction of cerebral blood flow and enhanced oxidative stress.
Inaba
Shinji
S
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan.
Iwai
Masaru
M
Tomono
Yumiko
Y
Senba
Izumi
I
Furuno
Megumi
M
Kanno
Harumi
H
Okayama
Hideki
H
Mogi
Masaki
M
Higaki
Jitsuo
J
Horiuchi
Masatsugu
M
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D002196:Capillaries / Q000473:pathology; D002560:Cerebrovascular Circulation; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis / Q000235:genetics; D012083:Renin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000808:Angiotensinogen; D013481:Superoxides; D000804:Angiotensin II; D000068756:Valsartan; D012083:Renin; D014633:Valine