RAGE mediates vascular injury and inflammation after global cerebral ischemia.
The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor involved in a diverse range of pathological conditions. To analyze the roles of RAGE and its decoy receptor, endogenous secretory RAGE (esRAGE), in the global cerebral ischemia, three different mouse cohorts, wild-type, RAGE⁻/⁻, and esRAGE transgenic (Tg) mice were subjected to bilateral common carotid artery occlusion (BCCAO). RT-PCR and immunohistochemical analysis revealed that expression of RAGE was induced in the vascular cells at 12 h, and then in the neurons and glia from 3 to 7 days in the hippocampus after BCCAO. The numbers of surviving neurons in the hippocampal CA1 region were significantly higher in RAGE⁻/⁻ and esRAGE Tg mice than those in wild-type mice in the periods between 24 h and 7 days after BCCAO. Lower levels of 3-nitrotyrosine (3-NT) and higher levels of endothelial nitric oxide synthase (eNOS), together with enlarged vascular areas were observed in RAGE⁻/⁻ and esRAGE Tg mice at 12 h after BCCAO. In the later periods, expressions of glia-derived inflammatory mediators TNFα and inducible nitric oxide synthase (iNOS) were reduced in RAGE⁻/⁻ and esRAGE Tg mice. These results suggest that RAGE may contribute to delayed neuronal death after global cerebral ischemia by enhancing vascular injury and deleterious glia-mediated inflammation.
Department of Neurosurgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan.
Tomoya
T
Kamide
Yasuko
Y
Kitao
Toshiaki
T
Takeichi
Akiko
A
Okada
Hiromi
H
Mohri
Ann Marie
AM
Schmidt
Takayuki
T
Kawano
Seiichi
S
Munesue
Yasuhiko
Y
Yamamoto
Hiroshi
H
Yamamoto
Jun-ichiro
J
Hamada
Osamu
O
Hori
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D020212:Carotid Artery Injuries / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009457:Neuroglia / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D018384:Oxidative Stress / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D020521:Stroke / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D057772:Vascular System Injuries / Q000473:pathology*
D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III