་ ඹ ᵝ ᘧ 㸯
Ꮫ ㄳ ồ ㄽ ᩥ ࡢ ෆ ᐜ ࡢ せ ᪨
ㄽ ᩥ ᥦ ฟ ⪅ Ặ ྡ ᚠ ⎔ ែ ⛉ Ꮫ 㡿 ᇦ ᚠ ⎔ ែ ෆ ⛉ Ꮫ ᩍ ⫱ ◊ ✲ ศ 㔝 Ặ ྡ ᕷ ᕝ ༤ ❶
㸦 ㄽ ᩥ 㢟 ┠ 㸧
Blood pressure-independent effect of olmesartan on albuminuria in mice overexpressing renin: Its beneficial role in the ACE2/Ang (1 -7)/Mas axis and NADPH oxidase expression
(ࣞ ࢽ ࣥ 㐣 Ⓨ ⌧ ࣐ ࢘ ࢫ ࡢ ᒀ ࣝ ࣈ ࣑ ࣥ ἥ ࠾ ࡅ ࡿ ࢜ ࣝ ࣓ ࢧ ࣝ ࢱ ࣥ
ࡢ ⾑ ᅽ 㠀 ౫ Ꮡ ⓗ ຠ ᯝ㸸ACE2 / Ang㸦1-7㸧/ Mas
⣔ ࠾ ࡼ ࡧNADPH
࢜ ࢟ ࢩ ࢲ ࣮ ࢮ Ⓨ ⌧ ཬ ࡰ ࡍ ࢜ ࣝ ࣓ ࢧ ࣝ ࢱ ࣥ ࡢ ᙳ 㡪)
⫼ ᬒ㸸ࣞ ࢽ ࣭ࣥ ࣥ ࢪ ࢜ ࢸ ࣥ ࢩ ࣥ ⣔
(RAS)ࡢ ㈿ ά ࡣ ⾑ ᅽ ୖ ᪼ ࢆ ច ㉳ ࡋ ࠊࡉ ࡽ ࣝ
ࣈ ࣑ ࣥ ᒀ ࡸ ⣒ ⌫ య ⫧ ࠸ ࡗ ࡓ ⭈ ⮚ ჾ 㞀 ᐖ ࢆ ᘬ ࡁ ㉳ ࡇ ࡍ ࠋ ࡋ ࡋ ࡑ ࡢ ᙳ 㡪 ࡀ ⾑ ᅽ ୖ
᪼ ㉳ ᅉ ࡍ ࡿ ࡶ ࡢ ࠊࡲ ࡓ ࡣ ࣥ ࢪ ࢜ ࢸ ࣥ ࢩ ࣥ
(Ang) II
ࡢ ㈿ ά ㉳ ᅉ ࡍ ࡿ ࡶ ࡢ ࡞ ࡢ ࡣ ᫂ ☜ ࡞ ࡗ ࡚ ࠸ ࡞ ࠸ ࠋ ࣥ ࢪ ࢜ ࢸ ࣥ ࢩ ࣥ ኚ 㓝 ⣲
2 (ACE2)/Ang(1-7)/Mas
ཷ ᐜ య ࢩ ࢢ ࢼ ࣝ ⤒ ㊰(ACE2/Ang(1-7)/Mas axis pathway)ࡣ RAS
ᣕ ᢠ ࡍ ࡿ ࡇ ࡼ ࡾ ⮚ ჾ 㞀 ᐖ ࡢ ᢚ ไ 㛵 ࡍ ࡿ ࡇ ࡀ ▱ ࡽ ࢀ ࡚ ࠾ ࡾ ࠊ ᪂ ࡋ ࠸ ⮚ ჾ 㞀 ᐖ ᢚ ไ ⤒ ㊰ ࡋ ࡚ ὀ ┠ ࡉ ࢀ࡚ ࠸ ࡿ ࠋ
┠ ⓗ 㸸 ⫢ ⮚ ࡽ ࣞ ࢽ ࣥ ࡀ 㐣 ศ Ἢ ࡉ ࢀ ࡿ 㑇 ఏ Ꮚ ᨵ ኚ ࣐ ࢘ ࢫ
(Ren-TG
࣐ ࢘ ࢫ) ࠊ 1
ᆺ ࣥ ࢪ ࢜ ࢸ ࣥ ࢩ ࣥ ཷ ᐜ య
(AT1R)
㜼 ᐖ ⸆ ࡋ ࡚ ᗈ ࡃ ⏝ ࠸ ࡽ ࢀ ࡚ ࠸ ࡿ ࢜ ࣝ ࣓ ࢧ ࣝ ࢱ ࣥ(Olm) ࢥ ࣥ ࢺ ࣟ ࣮ ࣝ ࡋ ࡚ ⾑ ⟶ ᣑ ᙇ ⸆ ࡛ ࠶ ࡿ ࣄ ࢻ ࣛ ࣛ ࢪ ࣥ (Hyd)ࢆ ᢞ ࡋ ࠊ㧗 ⾑ ᅽ ᛶ
⭈ ⮚ ჾ 㞀 ᐖ ࠾ ࡅ ࡿ
“ACE2/Ang(1-7)/Mas axis pathway”
࠾ ࡼ ࡧ 㓟 ࢫ ࢺ ࣞ ࢫ ࡢ ᙳ 㡪 ࡘ ࠸ ࡚ ᳨ ウ ࡋ ࡓ ࠋ
᪉ ἲ 㸸 㞝 㐌 㱋
16
㐌 ࡢRen-TG
࣐ ࢘ ࢫ(Ren)
㔝 ⏕ ᆺ ࣐ ࢘ ࢫ(WT)
Olm (5 mg/kg/day)
࠶ ࡿ ࠸ ࡣ
Hyd (3.5 mg/kg/day)
ࢆ 㣧 Ỉ ୰ ΰ ࡋ ᢞ ࡋ ࡓ ࠋ8 㐌 㛫 ᢞ ࡋ ࡓ ᚋ ⾑ ᅽ ࢆTelemetry
ἲ ࡛ ᐃ ࡋ ࠊ ௦ ㅰ ࢣ ࣮ ࢪ ࡚ ᒀ ࢆ ᅇ ࡋ ࠊ ࡑ ࡢ ᚋ ⭈ ⮚ ࢆ ฟ ࡋ ࡓ ࠋ ⭈ ⮚ ࠾ ࡅ ࡿ
mRNA
Ⓨ ⌧ 㔞 ࢆReal time PCR
࡛ ࠊࢱ ࣥ ࣃ ࢡ ㉁ Ⓨ ⌧ 㔞 ࢆWestern blot
࡛ ࡑ ࢀ ࡒࢀ ᐃ ࡋ ࡓ ࠋ㓟 ࢫ ࢺ ࣞ ࢫ ࡢ ᣦ ᶆ ࡛ ࠶ ࡿ ࢝ ࣝ ࣎ ࢽ ࣝ ࢱ ࣥ ࣃ ࢡ ࡣ
OxiSelect
TMProtein Carbonyl ELISA Kit
ࢆ ⏝ ࠸ ࡚ ᐃ ࡋ ࡓ ࠋ⤖ ᯝ㸸 ⦰ ᮇ ⾑ ᅽ ࡣ
Ren
⩌ ࡛WT
⩌ ẚ ㍑ ࡋ ᭷ ព ୖ ᪼ ࡋ ࡚ ࠸ ࡓ㸦158.2 ± 6.3 vs 112.8
± 8.8 mmHgࠊn = 3-4ࠊp <0.01㸧ࠋOlm
⩌ ࠾ ࡼ ࡧHyd
⩌ ࠾ ࡅ ࡿ ⦰ ᮇ ⾑ ᅽ ࡣ ࠸ ࡎ ࢀ ࡶWT
⩌ ྠ ⛬ ᗘ ࡲ ࡛ ప ୗ ࡋ ࡚ ࠸ ࡓ㸦123.5 ± 5.7 and 126.1 ± 6.5 mmHgࠊn = 3ࠊp<0.01㸧
ᒀ ࣝ ࣈ ࣑ ࣥ ἥ㸦UAE㸧ࡣ ࠊ Ren
⩌ ࡛WT
⩌ ẚ ㍑ ࡋ ࡚ ᭷ ព ቑ ຍ ࡋ ࡓ㸦78.2 ± 31.2 vs 28.6 ± 13.8 μg/dayࠊ n = 5-6ࠊp <0.01㸧ࠋ Olm
⩌ ࠾ ࡅ ࡿUAE
ࡣ20.3±5.2 μg/day
ࡲ࡛ ᭷ ព ῶ ᑡ ࡋ ࡓ㸦
n = 6ࠊp <0.01 vs Ren
⩌ 㸧ࡀ ࠊHyd ⩌ ࡛ ࡣ ῶ ᑡ ࡋ ࡞ ࡗ ࡓ㸦77.0 ± 41.8 μg/day
ࠊn = 6㸧ࠋ ⤌ ⧊ Ꮫ ⓗ ホ ౯ ࡛ ࡣ ࠊRen
⩌ ࡣ ⣒ ⌫ య ⫧ ࢆ ♧ ࡋ ࡓ ࡀ ࠊOlm
⩌ ࡛ ࡣ ⫧ ࡣ ᢚ ไ ࡉ ࢀ ࡓ ࠋ ୍ ᪉ ࠊHyd
⩌ ࡛ ࡣ ⣒ ⌫ య ⫧ ࡣ ᨵ ၿ ࡋ ࡞ ࡗ ࡓ ࠋRen
⩌ ࠾ ࡅ ࡿMas1
㑇 ఏ Ꮚ Ⓨ ⌧ ࡣ ࠊWT
⩌ ẚ ㍑ ࡋ ࡚ ᭷ ព ῶ ᑡ ࡋ ࡓ 㸦0.67 ± 0.07
ಸ ࠊp <0.05
ಸ ࠊn = 5㸧ࠋ Olm
⩌ ࠾ ࡅ ࡿMas 1
ࡢ 㑇 ఏ Ꮚ Ⓨ ⌧ ࡣWT
⩌ ྠ ⛬ ᗘ ࡲ ࡛ ᨵ ၿ ࡋ ࡓ ࡀ 㸦0.92 ± 0.10
ಸ ࠊn = 5㸧ࠊ Hyd
⩌ ࡛ ࡣ ᨵ ၿ ࡉ ࢀ ࡞ ࡗ ࡓ 㸦0.51 ± 0.10
ಸ ࠊn = 5
㸧ࠋRen
⩌ ࠾ ࡅ ࡿACE2
ࢱ ࣥ ࣃ ࢡ Ⓨ ⌧ ࡣ ࠊWT
⩌ ẚ ㍑ ࡋ ࡚ ᭷ ព ῶ ᑡ ࡋ ࡓ㸦0.76
± 0.07
ಸ ࠊn = 4ࠊ p <0.05
㸧ࠋOlm
⩌ ࠾ ࡅ ࡿACE2
ࢱ ࣥ ࣃ ࢡ Ⓨ ⌧ ࡣWT
⩌ ྠ ⛬ ᗘࡲ ࡛ ᨵ ၿ ࡋ ࡓ ࡀ 㸦
1.16 ± 0.12
ಸ ࠊn = 4㸧ࠊ Hyd
⩌ ࡛ ࡣ ᨵ ၿ ࡉ ࢀ ࡞ ࡗ ࡓ 㸦0.64 ± 0.13
ಸ ࠊn = 4㸧ࠋ
NADPH oxidase (Nox)ࡢ ά ᛶ ࡣ ࠊ Ang II
ࢩ ࢢ ࢼ ࣝ ࢆ ࡋ ࡓ 㓟 ࢫ ࢺ ࣞ ࢫ ⏕ ᡂ ࠾ ࠸࡚ せ ࡞ ᙺ ࢆ ᯝ ࡓ ࡋ ࡚ ࠸ ࡿ ࠋNox4 ࡢ ࢱ ࣥ ࣃ ࢡ Ⓨ ⌧ ࡣ
WT
⩌ ࡼ ࡾ ࡶRen
⩌ ࡛ ᭷ ព 㧗 ࡗ ࡓ㸦1.82 ± 0.49
ಸ ࠊn = 4ࠊp<0.05㸧ࠋ Olm
⩌ ࡛ ࡣNox4
ࢱ ࣥ ࣃ ࢡ ㉁ Ⓨ ⌧ ࡢ ቑ ຍ ࡀ ᭷ ព ᢚ ไ ࡉ ࢀ ࡚ ࠸ ࡓ 㸦0.86 ± 0.14
ಸ ࠊn = 4ࠊ p <0.01 vs Ren
⩌ 㸧 ࡀ ࠊHyd
⩌ ࡛ ࡣ ᢚ ไ ࡉ ࢀ ࡚ ࠸ ࡞ ࡗ ࡓ 㸦1.32 ± 0.37
ಸ ࠊn = 4㸧ࠋ
⭈ ⮚ ࠾ ࡅ ࡿ ࢱ ࣥ ࣃ ࢡ ㉁ ࢝ ࣝ ࣎ ࢽ ࣝ ࣞ ࣋ ࣝ ࡣ ࠊ
Ren
⩌ ࡛WT
⩌ ẚ ㍑ ࡋ ࡚ ᭷ ព ቑ ຍ ࡋ ࡚ ࠸ ࡓ 㸦0.34 ± 0.08 vs 0.15 ± 0.06 nmol/mgࠊ n = 4ࠊp <0.01㸧ࠋ Olm
⩌ ࡛ ࡣ ࡑ ࡢ ቑ ຍ ࡋ ࡓ ࢝ ࣝ ࣎ ࢽ ࣝ ࢱ ࣥ ࣃ ࢡ ࣞ ࣋ ࣝ ࡀ ῶ ᑡ ࡋ ࡚ ࠸ ࡓ㸦0.13 ± 0.03 nmol/mgࠊ n = 4ࠊ p <0.01 vs Ren
⩌ 㸧 ࡀ ࠊHyd
⩌ ࡛ ࡣ ῶ ᑡ ࡋ ࡚ ࠸ ࡞ ࡗ ࡓ 㸦0.36 ± 0.02 nmol/mgࠊ n = 4㸧ࠋ
⤖ ㄽ 㸸 ࢜ ࣝ ࣓ ࢧ ࣝ ࢱ ࣥ ࡣ ࠊ 㸯 ᆺ ࣥ ࢪ ࢜ ࢸ ࣥ ࢩ ࣥ ཷ ᐜ య ࢆ ᢚ ไ ࡍ ࡿ ࡔ ࡅ ࡛ ࡞ ࡃ ࠊ
ACE2/Ang(1-7)/Mas axis pathway
ࡢ ቑ ᙉ ࠾ ࡼ ࡧ 㓟 ࢫ ࢺ ࣞ ࢫ ⏕ ᡂ ࡢ ᢚ ไ ࢆ ࡋ ࡚ ࠊ ⾑ ᅽ ࡣ ↓ 㛵 ಀ ᒀ ࣝ ࣈ ࣑ ࣥ ἥ ࠾ ࡼ ࡧ ⣒ ⌫ య ⫧ ࢆ 㜼 ᐖ ࡍ ࡿ ࡇ ࡀ ♧ ၀ ࡉ ࢀ ࡓ ࠋͤ
1 எ ࡢ ሙ ྜ 㸪 ○○㡿 ᇦ ○○ᩍ ⫱ ◊ ✲ ศ 㔝 ࠼ ࡚ 㸪 ᡤ ᒓ ࡢ ○○
ㅮ ᗙ ࢆ グ ධ ࡍ ࡿ ࡇ ࠋͤ
