生体は親電子性物質，活性酸素種によって生成される酸化ストレスから生体を保護する応答システムを有している．Keap1（Kelch-like ECH-associated protein 1） -Nrf2（NF-E2 related factor2）システムがこの応答機構において重要な役割を果たす．核内移行したNrf2は転写因子として，NQO1，HO-1などの抗酸化遺伝子群の発現を制御する． 横紋筋融解症による急性腎障害（AKI: Acute Kidney Injury）の機序として，酸化ストレスが尿細管障害に大きく関与する．それ故，横紋筋融解症誘発性AKI においてもNrf2活性化による腎保護効果が期待される．横紋筋融解症誘発性AKI におけるNrf2活性化の意義と治療標的としての可能性を検討した．ヒト近位尿細管上皮細胞（hPTECs）を用いhemin 刺激に対するNrf2活性化の意義を検討した．hemin 刺激によりhPTECs におけるNrf2関連抗酸化遺伝子群の上昇，細胞障害を認めた．Nrf2-siRNA によるNrf2ノックダウン（KD）を行うことでhemin 刺激に対する抗酸化遺伝子群の発現上昇は抑制され，細胞障害が有意に増悪した．野生型マウス （WT），Nrf2欠損マウス（Nrf2KO）を用い，グリセロール筋注による横紋筋融解症モデルを作成した．（１）WT/Cont，（２）WT/ 横紋筋融解症（RM），（３）Nrf2KO/Cont，（４）Nrf2KO/RM の４群で比較検討した．結果は，WT/Cont に比べWT/RM 群で腎機能障害，尿細管障害，マクロファージ浸潤を認め，Nrf2KO/RM 群で有意に増悪した．抗酸化遺伝子群の発現はNrf2KO/RM 群で低下していた． 横紋筋融解症誘発性AKI において，Nrf2活性化が腎保護効果を有する事が示された．横紋筋融解症によるAKI に対して，Nrf2活性化が新たな治療標的となり得ることが明らかとなった．Cells are equipped with cytoprotective systems against oxidative stress caused by reactive oxygen species and electrophilic stress. The Keap1-Nrf2 pathway plays a central role in such mechanisms against oxidative and xenobiotic damage. Nrf2, as a transcription factor, activates a series of genes including NQO1 and HO-1.As the mechanism of acute kidney injury (AKI) due to rhabdomyolysis, renal tubule injury due to oxidative stress is the major component of the pathology. Therefore, in rhabdomyolysisinduced AKI, reno-protective effect of Nrf2 activation is expected. In the present study, the role of Nrf2 activation in rhabdomyolysis-induced AKI was investigated. In vitro, human proximal tubular epithelial cells (hPTECs) were used to determine the significance of Nrf2 for hemin stimulation. Hemin stimulation revealed elevation of Nrf2-related antioxidant gene group and cytotoxicity. Nrf2 knockdown (KD) with Nrf2-siRNA suppressed the rise of the expression of the antioxidant genes against hemin stimulation, and the cell damage was significantly exacerbated. A model of rhabdomyolysis by glycerol intramuscular injection was also prepared in vivo using wild type mice (WT) and Nrf2-deficient mice (Nrf2 KO). These mice were of the C57BL/6J background. We divided them into four groups: (1) WT/Cont, (2) WT/rhabdomyolysis (RM), (3) Nrf2 KO/Cont, and (4) Nrf2 KO/RM. Renal dysfunction and macrophage infiltration occurred more often in the WT/RM than in the WT/Cont, and it significantly worsened in the Nrf2 KO/RM group compared to the WT/RM. The expression of the antioxidant gene group was suppressed more in the Nrf2 KO/RM group compared with the WT/RM.These results indicate that Nrf2 activation exerts reno-protective effect in rhabdomyolysisinduced AKI. Nrf2 activation may be a new therapeutic target for rhabdomyolysis-induced AKI
