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Vagus nerve stimulation even after injury ameliorates cisplatininduced nephropathy via reducing macrophage infiltration

宇仁, 理恵 東京大学 DOI:10.15083/0002006995

2023.03.24

概要

[課程-2]
審査の結果の要旨
氏名 宇仁 理恵
本研究では、近年注目が高まっている抗炎症経路であるコリン作動性抗炎症経路
(CAP)の活性化による急性腎障害(AKI)に対する腎保護効果を検証した。現在 AKI の
治療は予防的な支持療法が中心であり、障害発生後に特に有効な治療法は確立していな
い。また、マウスの虚血再灌流障害(IRI)による AKI モデルでは事前の迷走神経刺激
(VNS)による CAP の活性化が腎保護効果をもたらすことが示されていることから、マ
ウスのシスプラチン腎症モデルを用いて事後の VNS の腎保護効果について検証を行い下
記の結果を得ている。
1. IRI に対する事後の VNS は無効であった。一方でシスプラチン腎症モデルでは事前
の VNS は腎保護効果を示さなかったが、既に腎障害が出現し始めているシスプラチ
ン投与 24 時間後に VNS を施した場合は有意な腎障害マーカーの低下と病理所見の改
善を認めた。これは腎障害モデルの違いによるものと考えられた。
2. CAP においては脾臓が重要な役割を果たしていることから、脾摘を行い同様の実験を
行ったところ脾摘をすると先述の VNS による腎保護効果は認められなかった。
3. また、CAP の中でα7ニコチン作動性アセチルコリン(α7nAChR)受容体を発現す
るマクロファージ(Mφ)が重要であることから選択的α7nAChR 作動薬である
GTS-21 で刺激した Mφをシスプラチン投与後に移注した。GTS-21 で刺激された M
φを投与された群で腎保護効果を認めた。
4. マウスの血中及び腎組織で種々のサイトカインを測定したところ、Mφの遊走に関わ
る CCL2 の発現が治療群で低下していた。腎組織への Mφの浸潤も病理及びフローサ
イトメトリー法により評価したところいずれも低下していたことから CAP の刺激が
CCL2 の発現を抑制し腎臓への炎症性 Mφの浸潤を抑制することで腎保護効果を発揮
することが示された。
以上、本論文はシスプラチンによる急性腎障害モデルにおいて、障害発生後であっても
VNS は CCL2 の発現を抑制し組織への炎症性 Mφの浸潤を低下させることで腎保護効果
を発揮することが示された。AKI は重症患者の重要な合併症の一つであり、それによる致
死率も高いことから VNS が AKI 発症後でも有効であれば多くの重症患者の利益となると
考えられる。VNS は低侵襲で他の疾患に対してはヒトへも応用されている技術であり、本
研究は腎臓領域への応用へ重要な貢献をすると考えられる。
よって本論文は博士( 医 学 )の学位請求論文として合格と認められる。

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